183 results on '"Nabuurs, S.B."'
Search Results
2. X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation
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Synofzik, M., Muller vom Hagen, M., Haack, T.B., Wilhelm, C., Lindig, T., Beck-Wodl, S., Nabuurs, S.B., Kuilenburg, A.B.P. van, Brouwer, A.P.M. de, and Schols, L.
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Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] - Abstract
Contains fulltext : 136163.pdf (Publisher’s version ) (Open Access) BACKGROUND: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), Arts syndrome, and non-syndromic sensorineural deafness (DFN2) are allelic syndromes, caused by reduced activity of phosphoribosylpyrophosphate synthetase 1 (PRS-I) due to loss-of-function mutations in PRPS1. As only few families have been described, knowledge about the relation between these syndromes, the phenotypic spectrum in patients and female carriers, and the relation to underlying PRS-I activity is limited. METHODS: We investigated a family with a novel PRPS1 mutation (c.830A > C, p.Gln277Pro) by extensive phenotyping, MRI, and genetic and enzymatic tests. RESULTS: The male index subject presented with an overlap of CMTX5 and Arts syndrome features, whereas his sister presented with prelingual DFN2. Both showed mild parietal and cerebellar atrophy on MRI. Enzymatically, PRS-I activity was undetectable in the index subject, reduced in his less affected sister, and normal in his unaffected mother. CONCLUSIONS: Our findings demonstrate that CMTX5, Arts syndrome and DFN2 are phenotypic clusters on an intrafamilial continuum, including overlapping phenotypes even within individuals. The respective phenotypic presentation seems to be determined by the exact PRPS1 mutation and the residual enzyme activity, the latter being largely influenced by the degree of skewed X-inactivation. Finally, our findings show that brain atrophy might be more common in PRPS1-disorders than previously thought.
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- 2014
3. Discovery of Small Molecule CD40-TRAF6 Inhibitors
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Zarzycka, B., Seijkens, T., Nabuurs, S.B., Ritschel, T., Grommes, J., Soehnlein, O., Schrijver, R., Tiel, C.M. Van, Hackeng, T.M., Weber, C., Giehler, F., Kieser, A., Lutgens, E., Vriend, G., Nicolaes, G.A., Zarzycka, B., Seijkens, T., Nabuurs, S.B., Ritschel, T., Grommes, J., Soehnlein, O., Schrijver, R., Tiel, C.M. Van, Hackeng, T.M., Weber, C., Giehler, F., Kieser, A., Lutgens, E., Vriend, G., and Nicolaes, G.A.
- Abstract
Item does not contain fulltext, The CD154-CD40 receptor complex plays a pivotal role in several inflammatory pathways. Attempts to inhibit the formation of this complex have resulted in systemic side effects. Downstream inhibition of the CD40 signaling pathway therefore seems a better way to ameliorate inflammatory disease. To relay a signal, the CD40 receptor recruits adapter proteins called tumor necrosis factor receptor-associated factors (TRAFs). CD40-TRAF6 interactions are known to play an essential role in several inflammatory diseases. We used in silico, in vitro, and in vivo experiments to identify and characterize compounds that block CD40-TRAF6 interactions. We present in detail our drug docking and optimization pipeline and show how we used it to find lead compounds that reduce inflammation in models of peritonitis and sepsis. These compounds appear to be good leads for drug development, given the observed absence of side effects and their demonstrated efficacy for peritonitis and sepsis in mouse models.
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- 2015
4. Structure based hypothesis of a mitochondrial ribosome rescue mechanism
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Huynen, M.A., Duarte, I., Chrzanowska-Lightowlers, Z.M., and Nabuurs, S.B.
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Energy and redox metabolism Mitochondrial medicine [NCMLS 4] - Abstract
Contains fulltext : 109616.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: mtRF1 is a vertebrate mitochondrial protein with an unknown function that arose from a duplication of the mitochondrial release factor mtRF1a. To elucidate the function of mtRF1, we determined the positions that are conserved among mtRF1 sequences but that are different in their mtRF1a paralogs. We subsequently modeled the 3D structure of mtRF1a and mtRF1 bound to the ribosome, highlighting the structural implications of these differences to derive a hypothesis for the function of mtRF1. RESULTS: Our model predicts, in agreement with the experimental data, that the 3D structure of mtRF1a allows it to recognize the stop codons UAA and UAG in the A-site of the ribosome. In contrast, we show that mtRF1 likely can only bind the ribosome when the A-site is devoid of mRNA. Furthermore, while mtRF1a will adopt its catalytic conformation, in which it functions as a peptidyl-tRNA hydrolase in the ribosome, only upon binding of a stop codon in the A-site, mtRF1 appears specifically adapted to assume this extended, peptidyl-tRNA hydrolyzing conformation in the absence of mRNA in the A-site. CONCLUSIONS: We predict that mtRF1 specifically recognizes ribosomes with an empty A-site and is able to function as a peptidyl-tRNA hydrolase in those situations. Stalled ribosomes with empty A-sites that still contain a tRNA bound to a peptide chain can result from the translation of truncated, stop-codon less mRNAs. We hypothesize that mtRF1 recycles such stalled ribosomes, performing a function that is analogous to that of tmRNA in bacteria. REVIEWERS: This article was reviewed by Dr. Eugene Koonin, Prof. Knud H. Nierhaus (nominated by Dr. Sarah Teichmann) and Dr. Shamil Sunyaev.
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- 2012
5. In Silico Veritas: The Pitfalls and Challenges of Predicting
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Roumen, L., Sanders, M.P.A., Vroling, B, de Esch, I.J.P., de Vlieg, J, Leurs, R., Klomp, J.P.G, Nabuurs, S.B., de Graaf, C., Medicinal chemistry, and AIMMS
- Abstract
Recently the first community-wide assessments of the prediction of the structures of complexes between proteins and small molecule ligands have been reported in the so-called GPCR Dock 2008 and 2010 assessments. In the current review we discuss the different steps along the protein-ligand modeling workflow by critically analyzing the modeling strategies we used to predict the structures of protein-ligand complexes we submitted to the recent GPCR Dock 2010 challenge. These representative test cases, focusing on the pharmaceutically relevant G Protein-Coupled Receptors, are used to demonstrate the strengths and challenges of the different modeling methods. Our analysis indicates that the proper performance of the sequence alignment, introduction of structural adjustments guided by experimental data, and the usage of experimental data to identify protein-ligand interactions are critical steps in the protein-ligand modeling protocol. © 2011 by the authors; licensee MDPI, Basel, Switzerland.
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- 2011
6. Application of a cell-based protease assay for testing inhibitors of picornavirus 3C proteases
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Linden, L. van der, Ulferts, R., Nabuurs, S.B., Kusov, Y., Liu, H., George, S., LaCroix, C., Goris, N., Lefebvre, D., Lanke, K.H.W., Clercq, K. De, Hilgenfeld, R., Neyts, J., Kuppeveld, F.J.M. van, Linden, L. van der, Ulferts, R., Nabuurs, S.B., Kusov, Y., Liu, H., George, S., LaCroix, C., Goris, N., Lefebvre, D., Lanke, K.H.W., Clercq, K. De, Hilgenfeld, R., Neyts, J., and Kuppeveld, F.J.M. van
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Item does not contain fulltext, Proteolytical cleavage of the picornaviral polyprotein is essential for viral replication. Therefore, viral proteases are attractive targets for anti-viral therapy. Most assays available for testing proteolytical activity of proteases are performed in vitro, using heterologously expressed proteases and peptide substrates. To deal with the disadvantages associated with in vitro assays, we modified a cell-based protease assay for picornavirus proteases. The assay is based on the induction of expression of a firefly luciferase reporter by a chimeric transcription factor in which the viral protease and cleavage sites are inserted between the GAL4 binding domain and the VP16 activation domain. Firefly luciferase expression is dependent on cleavage of the transcription factor by the viral protease. This biosafe assay enables testing the effect of compounds on protease activity in cells while circumventing the need for infection. We designed the assay for 3C proteases (3C(pro)) of various enteroviruses as well as of viruses of several other picornavirus genera, and show that the assay is amenable for use in a high-throughput setting. Furthermore, we show that the spectrum of activity of 3C(pro) inhibitor AG7088 (rupintrivir) not only encompasses enterovirus 3C(pro) but also 3C(pro) of foot-and-mouth disease virus (FMDV), an aphthovirus. In contrary, AG7404 (compound 1), an analogue of AG7088, had no effect on FMDV 3C(pro) activity, for which we provide a structural explanation.
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- 2014
7. A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy
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Brouwer, A.P.M. de, Nabuurs, S.B., Verhaart, I.E., Oudakker, A.R., Hordijk, R., Yntema, H.G., Hordijk-Hos, J.M., Voesenek, K.E., Vries, B. de, Essen, T. van, Chen, W., Hu, H, Chelly, J., Dunnen, J.T. den, Kalscheuer, V.M.M., Aartsma-Rus, A.M., Hamel, B.C.J., Bokhoven, H. van, Kleefstra, T., Brouwer, A.P.M. de, Nabuurs, S.B., Verhaart, I.E., Oudakker, A.R., Hordijk, R., Yntema, H.G., Hordijk-Hos, J.M., Voesenek, K.E., Vries, B. de, Essen, T. van, Chen, W., Hu, H, Chelly, J., Dunnen, J.T. den, Kalscheuer, V.M.M., Aartsma-Rus, A.M., Hamel, B.C.J., Bokhoven, H. van, and Kleefstra, T.
- Abstract
Item does not contain fulltext, We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with beta-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.
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- 2014
8. Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance
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Chatzigeorgiou, A., Seijkens, T., Zarzycka, B., Engel, D., Poggi, M., Berg, S. van den, Soehnlein, O., Winkels, H., Beckers, L., Lievens, D., Driessen, A., Kusters, P., Biessen, E.A., Garcia-Martin, R., Klotzsche-von Ameln, A., Gijbels, M., Noelle, R., Boon, L., Hackeng, T., Schulte, K.M., Xu, A., Vriend, G., Nabuurs, S.B., Chung, K.J., Willems van Dijk, K., Rensen, P.C., Gerdes, N., Winther, M.P. de, Block, N.L., Schally, A.V., Weber, C., Bornstein, S.R., Nicolaes, G., Chavakis, T., Lutgens, E., Chatzigeorgiou, A., Seijkens, T., Zarzycka, B., Engel, D., Poggi, M., Berg, S. van den, Soehnlein, O., Winkels, H., Beckers, L., Lievens, D., Driessen, A., Kusters, P., Biessen, E.A., Garcia-Martin, R., Klotzsche-von Ameln, A., Gijbels, M., Noelle, R., Boon, L., Hackeng, T., Schulte, K.M., Xu, A., Vriend, G., Nabuurs, S.B., Chung, K.J., Willems van Dijk, K., Rensen, P.C., Gerdes, N., Winther, M.P. de, Block, N.L., Schally, A.V., Weber, C., Bornstein, S.R., Nicolaes, G., Chavakis, T., and Lutgens, E.
- Abstract
Item does not contain fulltext
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- 2014
9. On the quality of NMR structures. Methodology and tools for NMR data and structure validation
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Nabuurs, S.B., Vriend, G., Vuister, G.W., and Radboud University Nijmegen
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Bioinformatics ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) - Abstract
Contains fulltext : 27386.pdf (Publisher’s version ) (Open Access) RU Radboud Universiteit Nijmegen, 09 februari 2006 Promotores : Vriend, G., Vuister, G.W. 144 p.
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- 2006
10. Traditional biomolecular structure determination by NMR spectroscopy allows for major errors
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Nabuurs, S.B., Spronk, C.A.E.M., Vuister, G.W., and Vriend, G.
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Chemical and physical biology [NCMLS 7] ,Bioinformatics ,Biophysical Chemistry ,Cellular energy metabolism [UMCN 5.3] - Abstract
Contains fulltext : 34563.pdf (Publisher’s version ) (Open Access) One of the major goals of structural genomics projects is to determine the three-dimensional structure of representative members of as many different fold families as possible. Comparative modeling is expected to fill the remaining gaps by providing structural models of homologs of the experimentally determined proteins. However, for such an approach to be successful it is essential that the quality of the experimentally determined structures is adequate. In an attempt to build a homology model for the protein dynein light chain 2A (DLC2A) we found two potential templates, both experimentally determined nuclear magnetic resonance (NMR) structures originating from structural genomics efforts. Despite their high sequence identity (96%), the folds of the two structures are markedly different. This urged us to perform in-depth analyses of both structure ensembles and the deposited experimental data, the results of which clearly identify one of the two models as largely incorrect. Next, we analyzed the quality of a large set of recent NMR-derived structure ensembles originating from both structural genomics projects and individual structure determination groups. Unfortunately, a visual inspection of structures exhibiting lower quality scores than DLC2A reveals that the seriously flawed DLC2A structure is not an isolated incident. Overall, our results illustrate that the quality of NMR structures cannot be reliably evaluated using only traditional experimental input data and overall quality indicators as a reference and clearly demonstrate the urgent need for a tight integration of more sophisticated structure validation tools in NMR structure determination projects. In contrast to common methodologies where structures are typically evaluated as a whole, such tools should preferentially operate on a per-residue basis.
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- 2006
11. RECOORD: a recalculated coordinate database of 500+ proteins from the PDB using restraints from the BioMagResBank
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Nederveen, A.J., Doreleijers, J.F., Vranken, W., Miller, Z., Spronk, C.A.E.M., Nabuurs, S.B., Guntert, P., Livny, M., Markley, J.L., Nilges, M., Ulrich, E.L., Kaptein, R., Bonvin, A.M.J.J., NMR-spectroscopie, NMR Spectroscopy 1, Dep Scheikunde, Other departments, and Department of Bio-engineering Sciences
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Bioinformatics ,Computer science ,Protein Conformation ,Protein Data Bank (RCSB PDB) ,010402 general chemistry ,computer.software_genre ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Structural Biology ,Taverne ,Databases, Protein ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Database ,biology ,Proteins ,Reproducibility of Results ,Structure validation ,computer.file_format ,Cyana ,biology.organism_classification ,Protein Data Bank ,Solution structure ,0104 chemical sciences ,Weak correlation ,International ,Reference database ,Data mining ,Stress, Mechanical ,Cellular energy metabolism [UMCN 5.3] ,computer ,Ramachandran plot - Abstract
State-of-the-art methods based on CNS and CYANA were used to recalculate the nuclear magnetic resonance (NMR) solution structures of 500 proteins for which coordinates and NMR restraints are available from the Protein Data Bank. Curated restraints were obtained from the BioMagResBank FRED database. Although the original NMR struc- tures were determined by various methods, they all were recalculated by CNS and CYANA and refined subsequently by restrained molecular dynamics (CNS) in a hydrated environment. We present an extensive analysis of the results, in terms of various quality indicators generated by PROCHECK and WHAT- _CHECK. On average, the quality indicators for pack- ing and Ramachandran appearance moved one stan- dard deviation closer to the mean of the reference database. The structural quality of the recalculated structures is discussed in relation to various parame- ters, including number of restraints per residue, NOE completeness and positional root mean square devia- tion (RMSD). Correlations between pairs of these quality indicators were generally low; for example, there is a weak correlation between the number of restraints per residue and the Ramachandran appear- ance according to WHAT_CHECK (r 0.31). The set of recalculated coordinates constitutes a unified data- base of protein structures in which potential user- and software-dependent biases have been kept as small as possible. The database can be used by the structural biology community for further develop- ment of calculation protocols, validation tools, struc- ture-based statistical approaches and modeling. The RECOORD database of recalculated structures is pub- licly available from http://www.ebi.ac.uk/msd/reco
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- 2005
12. RECOORD: a Recalculated COORdinates Database of 500+ proteins from PDB using restraints from the BioMagResBank
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Nederveen, A.J., Doreleijers, J.F., Vranken, W., Miller, Z., Spronk, C.A.E.M., Nabuurs, S.B., Guntert, P., Livny, M., Markley, J.L., Nilges, M., Ulrich, E.L., Kaptein, R., Bonvin, A.M.J.J., NMR-spectroscopie, NMR Spectroscopy 1, and Dep Scheikunde
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International ,Taverne - Abstract
State‐of‐the‐art methods based on CNS and CYANA were used to recalculate the nuclear magnetic resonance (NMR) solution structures of 500+ proteins for which coordinates and NMR restraints are available from the Protein Data Bank. Curated restraints were obtained from the BioMagResBank FRED database. Although the original NMR structures were determined by various methods, they all were recalculated by CNS and CYANA and refined subsequently by restrained molecular dynamics (CNS) in a hydrated environment. We present an extensive analysis of the results, in terms of various quality indicators generated by PROCHECK and WHAT_CHECK. On average, the quality indicators for packing and Ramachandran appearance moved one standard deviation closer to the mean of the reference database. The structural quality of the recalculated structures is discussed in relation to various parameters, including number of restraints per residue, NOE completeness and positional root mean square deviation (RMSD). Correlations between pairs of these quality indicators were generally low; for example, there is a weak correlation between the number of restraints per residue and the Ramachandran appearance according to WHAT_CHECK (r = 0.31). The set of recalculated coordinates constitutes a unified database of protein structures in which potential user‐ and software‐dependent biases have been kept as small as possible. The database can be used by the structural biology community for further development of calculation protocols, validation tools, structure‐based statistical approaches and modeling. The RECOORD database of recalculated structures is publicly available from http://www.ebi.ac.uk/msd/recoord. Proteins 2005.
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- 2005
13. DRESS: a database of refined solution NMR structures
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Nabuurs, S.B., Nederveen, A.J., Vranken, W., Doreleijers, J.F., Bonvin, A.M.J.J., Vuister, G.W., Vriend, G., Spronk, C.A.E.M., NMR-spectroscopie, NMR Spectroscopy 1, Dep Scheikunde, NMR-spectroscopie, NMR Spectroscopy 1, Dep Scheikunde, Department of Bio-engineering Sciences, and Other departments
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Models, Molecular ,Database ,Bioinformatics ,Chemistry ,Structure validation ,Nuclear magnetic resonance crystallography ,computer.software_genre ,Biochemistry ,proteins ,Set (abstract data type) ,Structural Biology ,Taverne ,Solvents ,Biophysical Chemistry ,Cellular energy metabolism [UMCN 5.3] ,Databases, Protein ,Molecular Biology ,computer ,Nuclear Magnetic Resonance, Biomolecular - Abstract
Contains fulltext : 57416.pdf (Publisher’s version ) (Closed access) Several studies have shown that biomolecular NMR structures are often of lower quality when compared to crystal structures, and consequently they are often excluded from structural analyses. We present a publicly available database of re-refined NMR structures, exhibiting significantly improved quality. This database (available at http://www.cmbi.kun.nl/dress/) presents a uniformly refined and validated set of structural models that improves the value of these NMR structures as input for experimental and theoretical studies in many fields of research.
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- 2004
14. The precision of NMR structure ensembles revisited
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Spronk, C.A.E.M., Nabuurs, S.B., Bonvin, A.M., Krieger, E., Vuister, G.W., Vriend, G., NMR-spectroscopie, NMR Spectroscopy 1, and Dep Scheikunde
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Bioinformatics ,Taverne ,Biophysical Chemistry ,Cellular energy metabolism [UMCN 5.3] - Abstract
Contains fulltext : 79477.pdf (Publisher’s version ) (Closed access) Biomolecular structures provide the basis for many studies in research areas such as structure-based drug design and homology modeling. In order to use molecular coordinates it is important that they are reliable in terms of accurate description of the experimental data and in terms of the overall and local geometry. Besides these primary quality criteria an indication is needed for the uncertainty in the atomic coordinates that may arise from the dynamic behavior of the considered molecules as well as from experimental- and computational procedures.In contrast to the crystallographic B-factor, a good measure for the uncertainty in NMR-derived atomic coordinates is still not available. It has become clear in recent years that the widely used atomic Root Mean Square Deviation (RMSD), which is a measure for the precision of the data, overestimates the accuracy of NMR structure ensembles and therefore is a problematic measure for the uncertainty in the atomic coordinates.In this study we report a method that yields a more realistic estimate of the uncertainty in the atomic coordinates by maximizing the RMSD of an ensemble of structures, while maintaining the accordance with the experimentally derived data. The results indicate that the RMSD of most NMR structure ensembles can be significantly increased compromising neither geometric quality nor NMR data. This maximized RMSD therefore seems a better estimate of the true uncertainty in the atomic coordinates.
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- 2003
15. A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy
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Jonckheere, A.I., Renkema, G.H., Bras, M., Heuvel, L.P.W.J. van den, Hoischen, A., Gilissen, C.F.H.A., Nabuurs, S.B., Huynen, M.A., Vries, M.C. de, Smeitink, J.A.M., Rodenburg, R.J.T., Jonckheere, A.I., Renkema, G.H., Bras, M., Heuvel, L.P.W.J. van den, Hoischen, A., Gilissen, C.F.H.A., Nabuurs, S.B., Huynen, M.A., Vries, M.C. de, Smeitink, J.A.M., and Rodenburg, R.J.T.
- Abstract
Item does not contain fulltext, Whole exome sequencing is a powerful tool to detect novel pathogenic mutations in patients with suspected mitochondrial disease. However, the interpretation of novel genetic variants is not always straightforward. Here, we present two siblings with a severe neonatal encephalopathy caused by complex V deficiency. The aim of this study was to uncover the underlying genetic defect using the combination of enzymatic testing and whole exome sequence analysis, and to provide evidence for causality by functional follow-up. Measurement of the oxygen consumption rate and enzyme analysis in fibroblasts were performed. Immunoblotting techniques were applied to study complex V assembly. The coding regions of the genome were analysed. Three-dimensional modelling was applied. Exome sequencing of the two siblings with complex V deficiency revealed a heterozygous mutation in the ATP5A1 gene, coding for complex V subunit alpha. The father carried the variant heterozygously. At the messenger RNA level, only the mutated allele was expressed in the patients, whereas the father expressed both the wild-type and the mutant allele. Gene expression data indicate that the maternal allele is not expressed, which is supported by the observation that the ATP5A1 expression levels in the patients and their mother are reduced to approximately 50%. Complementation with wild-type ATP5A1 restored complex V in the patient fibroblasts, confirming pathogenicity of the defect. At the protein level, the mutation results in a disturbed interaction of the alpha-subunit with the beta-subunit of complex V, which interferes with the stability of the complex. This study demonstrates the important value of functional studies in the diagnostic work-up of mitochondrial patients, in order to guide genetic variant prioritization, and to validate gene defects.
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- 2013
16. A functional variant in the CFI gene confers a high risk of age-related macular degeneration.
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Ven, J.P.H. van de, Nilsson, S.C., Tan, P.L., Buitendijk, G.H., Ristau, T., Mohlin, F.C., Nabuurs, S.B., Schoenmaker-Koller, F.E., Smailhodzic, D., Campochiaro, P.A., Zack, D.J., Duvvari, M.R., Bakker, B., Paun, C.C., Boon, C.J.F., Uitterlinden, A.G., Liakopoulos, S., Klevering, B.J., Fauser, S., Daha, M.R., Katsanis, N., Klaver, C.C., Blom, A.M., Hoyng, C.B., Hollander, A.I. den, Ven, J.P.H. van de, Nilsson, S.C., Tan, P.L., Buitendijk, G.H., Ristau, T., Mohlin, F.C., Nabuurs, S.B., Schoenmaker-Koller, F.E., Smailhodzic, D., Campochiaro, P.A., Zack, D.J., Duvvari, M.R., Bakker, B., Paun, C.C., Boon, C.J.F., Uitterlinden, A.G., Liakopoulos, S., Klevering, B.J., Fauser, S., Daha, M.R., Katsanis, N., Klaver, C.C., Blom, A.M., Hoyng, C.B., and Hollander, A.I. den
- Abstract
Item does not contain fulltext, Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 x 10(-6); odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.
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- 2013
17. Design and application of structure-based pharmacophores for class A GPCRs
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Vlieg, J. de, Nabuurs, S.B., Sanders, M.P.A., Vlieg, J. de, Nabuurs, S.B., and Sanders, M.P.A.
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Radboud Universiteit Nijmegen, 20 juni 2012, Promotor : Vlieg, J. de Co-promotor : Nabuurs, S.B., Contains fulltext : 93565.pdf (publisher's version ) (Open Access)
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- 2012
18. Flexible protein-ligand docking using the fleksy protocol
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Wagener, M., Vlieg, J. de, Nabuurs, S.B., Wagener, M., Vlieg, J. de, and Nabuurs, S.B.
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Item does not contain fulltext
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- 2012
19. Enzyme-Specific Activation versus Leaving Group Ability.
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Beer, R.J.A.C. de, Bogels, B., Schaftenaar, G., Zarzycka, B., Quaedflieg, P.J.L.M., Delft, F.L. van, Nabuurs, S.B., Rutjes, F.P.J.T., Beer, R.J.A.C. de, Bogels, B., Schaftenaar, G., Zarzycka, B., Quaedflieg, P.J.L.M., Delft, F.L. van, Nabuurs, S.B., and Rutjes, F.P.J.T.
- Abstract
Contains fulltext : 103347.pdf (publisher's version ) (Closed access), Enzyme-specific activation and the substrate mimetics strategy are effective ways to circumvent the limited substrate recognition often encountered in protease-catalyzed peptide synthesis. A key structural element in both approaches is the guanidinophenyl (OGp) ester, which enables important interactions for affinity and recognition by the enzyme-at least, this is usually the explanation given for its successful application. In this study we show that leaving group ability is of equal or even greater importance. To this end we used both experimental and computational methods: 1) synthesis of close analogues of OGp, and their evaluation in a dipeptide synthesis assay with trypsin, 2) molecular docking studies to provide insights into the binding mode, and 3) ab initio calculations to evaluate their electronic properties.
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- 2012
20. CING: an integrated residue-based structure validation program suite
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Doreleijers, J., Sousa da Silva, A.W., Krieger, E., Nabuurs, S.B., Spronk, C.A.E.M., Stevens, T.J., Vranken, W.F., Vriend, G., Vuister, G.W., Doreleijers, J., Sousa da Silva, A.W., Krieger, E., Nabuurs, S.B., Spronk, C.A.E.M., Stevens, T.J., Vranken, W.F., Vriend, G., and Vuister, G.W.
- Abstract
Item does not contain fulltext, We present a suite of programs, named CING for Common Interface for NMR Structure Generation that provides for a residue-based, integrated validation of the structural NMR ensemble in conjunction with the experimental restraints and other input data. External validation programs and new internal validation routines compare the NMR-derived models with empirical data, measured chemical shifts, distance- and dihedral restraints and the results are visualized in a dynamic Web 2.0 report. A red-orange-green score is used for residues and restraints to direct the user to those critiques that warrant further investigation. Overall green scores below ~20 % accompanied by red scores over ~50 % are strongly indicative of poorly modelled structures. The publically accessible, secure iCing webserver ( https://nmr.le.ac.uk ) allows individual users to upload the NMR data and run a CING validation analysis.
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- 2012
21. Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I.
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Moran, R., Kuilenburg, A.B.P. van, Duley, J., Nabuurs, S.B., Retno-Fitri, A., Christodoulou, J., Roelofsen, J., Yntema, H.G., Friedman, N.R., Bokhoven, J.H.L.M. van, Brouwer, A.P.M. de, Moran, R., Kuilenburg, A.B.P. van, Duley, J., Nabuurs, S.B., Retno-Fitri, A., Christodoulou, J., Roelofsen, J., Yntema, H.G., Friedman, N.R., Bokhoven, J.H.L.M. van, and Brouwer, A.P.M. de
- Abstract
1 februari 2012, Item does not contain fulltext, We identified a novel missense mutation, c.424G>C (p.Val142Leu) in PRPS1 in a patient with uric acid overproduction without gout but with developmental delay, hypotonia, hearing loss, and recurrent respiratory infections. The uric acid overproduction accompanying this combination of symptoms suggests that the patient presented with phosphoribosylpyrophosphate (PRPP) synthetase superactivity, but recurrent infections have not been associated with superactivity until now. However, recurrent infections are a prominent feature of patients with Arts syndrome, which is caused by PRPS1 loss-of-function mutations, indicating that the patient reported here has an intermediate phenotype. Molecular modeling predicts that the p.Val142Leu change affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of-function of PRPP synthetase. This finding is in line with the normal PRPP synthetase activity in fibroblasts and the absence of activity in erythrocytes of the present patient. We postulate that the overall effect of the p.Val142Leu change on protein activity is determined by the cell type, being a gain-of-function in proliferating cells and a loss-of-function in postmitotic cells. Our results show that missense mutations in PRPS1 can cause a continuous spectrum of features ranging from progressive non-syndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites that are affected.
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- 2012
22. Chemoenzymatic peptide synthesis through enzyme-specific activition
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Rutjes, F.P.J.T., Nabuurs, S.B., Delft, F.L. van, Beer, R.J.A.C. de, Rutjes, F.P.J.T., Nabuurs, S.B., Delft, F.L. van, and Beer, R.J.A.C. de
- Abstract
Radboud Universiteit Nijmegen, 5 september 2012, Promotor : Rutjes, F.P.J.T. Co-promotores : Nabuurs, S.B., Delft, F.L. van, Contains fulltext : 94178.pdf (publisher's version ) (Open Access)
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- 2012
23. In Silico Identification of Potential Cholestasis-Inducing Agents via Modeling of Na+-Dependent Taurocholate Cotransporting Polypeptide Substrate Specificity.
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Greupink, R., Nabuurs, S.B., Zarzycka, B., Verweij, V.G.M., Monshouwer, M., Huisman, M.T., Russel, F.G.M., Greupink, R., Nabuurs, S.B., Zarzycka, B., Verweij, V.G.M., Monshouwer, M., Huisman, M.T., and Russel, F.G.M.
- Abstract
01 september 2012, Contains fulltext : 108286.pdf (publisher's version ) (Closed access), Na(+)-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1) is the main transporter facilitating the hepatic uptake of bile acids from the circulation. Consequently, the interaction of xenobiotics, including therapeutic drugs, with the bile acid binding pocket of NTCP could lead to impairment of hepatic bile acid uptake. We pursued a 3D-pharmacophore approach to model the NTCP substrate and inhibitor specificity and investigated whether it is possible to identify compounds with intrinsic NTCP inhibitory properties. Based on known endogenous NTCP substrates, a 3D-pharmacophore model was built, which was subsequently used to screen two virtual libraries together containing the structures of 10 million compounds. Studies with Chinese hamster ovary cells overexpressing human NTCP, human hepatocytes, ex vivo perfused rat livers, and bile duct-cannulated rats were conducted to validate the activity of the virtual screening hits. Modeling yielded a 3D-pharmacophore, consisting of two hydrogen bond acceptors and three hydrophobic features. Six out of 10 structurally diverse compounds selected in the first virtual screening procedure significantly inhibited taurocholate uptake in the NTCP overexpressing cells. For the most potent inhibitor identified, an anthraquinone derivative, this finding was confirmed in human hepatocytes and perfused rat livers. Subsequent structure and activity relationship studies with analogs of this derivative indicated that an appropriate distance between hydrogen bond acceptor features and presence of one or two negative charges appear critical for a successful NTCP interaction. In conclusion, pharmacophore modeling was successfully used to identify compounds that inhibit NTCP. Our approach represents an important first step toward the in silico flagging of potential cholestasis-inducing molecules.
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- 2012
24. Papain-specific activating esters in aqueous dipeptide synthesis.
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Beer, R.J. de, Zarzycka, B., Mariman, M., Amatdjais-Groenen, H., Mulders, M.J., Quaedflieg, P.J.L.M., Delft, F.L. van, Nabuurs, S.B., Rutjes, F.P.J.T., Beer, R.J. de, Zarzycka, B., Mariman, M., Amatdjais-Groenen, H., Mulders, M.J., Quaedflieg, P.J.L.M., Delft, F.L. van, Nabuurs, S.B., and Rutjes, F.P.J.T.
- Abstract
Contains fulltext : 103605.pdf (Publisher’s version ) (Open Access), Enzymatic peptide synthesis has the potential to be a viable alternative for chemical peptide synthesis. Because of the increasing commercial interest in peptides, new and improved enzymatic synthesis methods are desirable. In recently developed enzymatic strategies such as substrate mimetic approaches and enzyme-specific activation, use of the guanidinophenyl ester (OGp) group has been shown to suffer from some drawbacks. OGp esters are sensitive to spontaneous chemical hydrolysis and the group is expensive to synthesize and therefore not suitable for large-scale applications. On the basis of earlier computational studies, we hypothesized that OGp might be replaceable by simpler ester groups to make the enzyme-specific activation approach to peptide bond formation more accessible. To this end, a set of potential activating esters (Z-Gly-Act) was designed, synthesized, and evaluated. Both the benzyl (OBn) and the dimethylaminophenyl (ODmap) esters gave promising results. For these esters, the scope of a model dipeptide synthesis reaction under aqueous conditions was investigated by varying the amino acid donor. The results were compared with those obtained from a previous study of Z-X(AA) -OGp esters. Computational docking analysis of the set of esters was performed in order to provide insight into the differences in the reactivities of all the potential activating esters. Finally, selected ODmap- and OBn-activated amino acids were applied in the synthesis of two biologically active dipeptides on preparative scales.
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- 2012
25. Papain-specific activating esters in aqueous dipeptide synthesis
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Beer, R.J.A.C. de, Zarzycka, B., Mariman, M., Amatdjais-Groenen, H.I.V., Mulders, M.J., Quaedflieg, P.J.L.M., Delft, F.L. van, Nabuurs, S.B., Rutjes, F.P.J.T., Beer, R.J.A.C. de, Zarzycka, B., Mariman, M., Amatdjais-Groenen, H.I.V., Mulders, M.J., Quaedflieg, P.J.L.M., Delft, F.L. van, Nabuurs, S.B., and Rutjes, F.P.J.T.
- Abstract
Item does not contain fulltext
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- 2012
26. Evolution and diversification of the organellar release factor family
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Dos Santos Duarte, G.I., Nabuurs, S.B., Magno, R., Huynen, M.A., Dos Santos Duarte, G.I., Nabuurs, S.B., Magno, R., and Huynen, M.A.
- Abstract
Item does not contain fulltext, Translation termination is accomplished by proteins of the Class I release factor family (RF) that recognize stop codons and catalyze the ribosomal release of the newly synthesized peptide. Bacteria have two canonical RFs: RF1 recognizes UAA and UAG, RF2 recognizes UAA and UGA. Despite that these two release factor proteins are sufficient for de facto translation termination, the eukaryotic organellar RF protein family, which has evolved from bacterial release factors, has expanded considerably, comprising multiple subfamilies, most of which have not been functionally characterized or formally classified. Here, we integrate multiple sources of information to analyze the remarkable differentiation of the RF family among organelles. We document the origin, phylogenetic distribution and sequence structure features of the mitochondrial and plastidial release factors: mtRF1a, mtRF1, mtRF2a, mtRF2b, mtRF2c, ICT1, C12orf65, pRF1, and pRF2, and review published relevant experimental data. The canonical release factors (mtRF1a, mtRF2a, pRF1, and pRF2) and ICT1 are derived from bacterial ancestors, whereas the others have resulted from gene duplications of another release factor. These new RF family members have all lost one or more specific motifs relevant for bona fide release factor function but are mostly targeted to the same organelle as their ancestor. We also characterize the subset of canonical release factor proteins that bear nonclassical PxT/SPF tripeptide motifs and provide a molecular-model-based rationale for their retained ability to recognize stop codons. Finally, we analyze the coevolution of canonical RFs with the organellar genetic code. Although the RF presence in an organelle and its stop codon usage tend to coevolve, we find three taxa that encode an RF2 without using UGA stop codons, and one reverse scenario, where mamiellales green algae use UGA stop codons in their mitochondria without having a mitochondrial type RF2. For the latter, we put forward a
- Published
- 2012
27. NDUFB7 and NDUFA8 are located at the intermembrane surface of complex I
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Szklarczyk, R.J., Wanschers, B.F.J., Nabuurs, S.B., Nouws, J., Nijtmans, L.G.J., Huynen, M.A., Szklarczyk, R.J., Wanschers, B.F.J., Nabuurs, S.B., Nouws, J., Nijtmans, L.G.J., and Huynen, M.A.
- Abstract
Contains fulltext : 98132.pdf (publisher's version ) (Closed access), Complex I (NADH:ubiquinone oxidoreductase) is the first and largest protein complex of the oxidative phosphorylation. Crystal structures have elucidated the positions of most subunits of bacterial evolutionary origin in the complex, but the positions of the eukaryotic subunits are unknown. Based on the analysis of sequence conservation we propose intra-molecular disulfide bridges and the inter-membrane space localization of three Cx(9)C-containing subunits in human: NDUFS5, NDUFB7 and NDUFA8. We experimentally confirm the localization of the latter two, while our data are consistent with disulfide bridges in NDUFA8. We propose these subunits stabilize the membrane domain of complex I.
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- 2011
28. Gaussian interaction profile kernels for predicting drug–target interaction
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Laarhoven, T.M. van, Nabuurs, S.B., Marchiori, E., Laarhoven, T.M. van, Nabuurs, S.B., and Marchiori, E.
- Abstract
4 september 2011, Contains fulltext : 91847.pdf (publisher's version ) (Closed access)
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- 2011
29. Papain-catalyzed peptide bond formation: Enzyme-specific activation with guanidinophenyl esters
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Beer, R. de, Zarzycka, B., Amatdjais-Groenen, H.I.V., Jans, S.C.B., Nuijens, T., Quaedflieg, P.J.L.M., Delft, F.L. van, Nabuurs, S.B., Rutjes, F.P.J.T., Beer, R. de, Zarzycka, B., Amatdjais-Groenen, H.I.V., Jans, S.C.B., Nuijens, T., Quaedflieg, P.J.L.M., Delft, F.L. van, Nabuurs, S.B., and Rutjes, F.P.J.T.
- Abstract
Contains fulltext : 92174.pdf (publisher's version ) (Closed access)
- Published
- 2011
30. In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions.
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Roumen, L., Sanders, M.P.A., Vroling, B., Esch, I.J. de, Vlieg, J. de, Leurs, R., Klomp, J.P.G., Nabuurs, S.B., Graaf, C. de, Roumen, L., Sanders, M.P.A., Vroling, B., Esch, I.J. de, Vlieg, J. de, Leurs, R., Klomp, J.P.G., Nabuurs, S.B., and Graaf, C. de
- Abstract
Contains fulltext : 91925.pdf (publisher's version ) (Open Access)
- Published
- 2011
31. Snooker: a structure-based pharmacophore generation tool applied to class A GPCRs.
- Author
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Sanders, M.P.A., Verhoeven, S., Graaf, C. de, Roumen, L., Vroling, B., Nabuurs, S.B., Vlieg, J. de, Klomp, J.P.G., Sanders, M.P.A., Verhoeven, S., Graaf, C. de, Roumen, L., Vroling, B., Nabuurs, S.B., Vlieg, J. de, and Klomp, J.P.G.
- Abstract
Contains fulltext : 92346.pdf (publisher's version ) (Closed access)
- Published
- 2011
32. PRPS1 mutations: four distinct syndromes and potential treatment.
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Brouwer, A.P.M. de, Bokhoven, J.H.L.M. van, Nabuurs, S.B., Arts, W.F.M., Christodoulou, J., Duley, J., Brouwer, A.P.M. de, Bokhoven, J.H.L.M. van, Nabuurs, S.B., Arts, W.F.M., Christodoulou, J., and Duley, J.
- Abstract
Contains fulltext : 89878.pdf (publisher's version ) (Closed access), Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in phosphoribosylpyrophosphate synthetase 1 (PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data).
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- 2010
33. PRPS1 Mutations: Four Distinct Syndromes and Potential Treatment
- Author
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Brouwer, A.P.M. (Arjan) de, Bokhoven, H. (Hans) van, Nabuurs, S.B. (Sander), Arts, W.F.M. (Willem Frans), Christodoulou, J. (John), Duley, J. (John), Brouwer, A.P.M. (Arjan) de, Bokhoven, H. (Hans) van, Nabuurs, S.B. (Sander), Arts, W.F.M. (Willem Frans), Christodoulou, J. (John), and Duley, J. (John)
- Abstract
Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in phosphoribosylpyrophosphate synthetase 1 (PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data).
- Published
- 2010
- Full Text
- View/download PDF
34. Two divergent leptin paralogues in zebrafish (Danio rerio) that originate early in teleostean evolution.
- Author
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Gorissen, M.H.A.G., Bernier, N.J., Nabuurs, S.B., Flik, G., Huising, M.O., Gorissen, M.H.A.G., Bernier, N.J., Nabuurs, S.B., Flik, G., and Huising, M.O.
- Abstract
Contains fulltext : 81041.pdf (postprint version ) (Open Access) Contains fulltext : 81041.pdf (preprint version ) (Open Access), We describe duplicate leptin genes in zebrafish (Danio rerio) that share merely 24% amino acid identity with each other and only 18% with human leptin. We were also able to retrieve a second leptin gene in medaka (Oryzias latipes). The presence of duplicate leptin genes in these two distantly related teleosts suggests that duplicate leptin genes are a common feature of teleostean fishes. Despite low primary sequence conservation, we are confident in assigning orthology between mammalian and zebrafish leptins for several reasons. First, both zebrafish leptins share their characteristic gene structure and display key features of conserved synteny with mammalian leptin genes. Secondly, the cysteine residues that make up leptin's single disulphide bridge are equally spaced in mammalian and zebrafish leptins and are unique among all members of the class-I helical cytokine family. Thirdly, the zebrafish leptins cluster with other fish leptins and mammalian leptins in phylogenetic analysis, supported by high bootstrap values. Within the leptin cluster, leptin-b forms a separate clade with the leptin-b orthologue from medaka. Finally, our prediction of the tertiary structures shows that both leptins conform to the typical four alpha-helix bundle structure of the class-I alpha-helical cytokines. The zebrafish leptins are differentially expressed; the liver shows high leptin-a expression (in concordance with what we observed for carp leptins), while leptin-b is expressed at much lower levels, which are downregulated further upon fasting. The finding of duplicate leptin genes in teleosts adds to our understanding of the evolution of leptin physiology in the early vertebrate lineage.
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- 2009
35. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders.
- Author
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Thiadens, A.A.H.J., Hollander, A.I. den, Roosing, S., Nabuurs, S.B., Zekveld-Vroon, R.C., Collin, R.W.J., Baere, E. de, Koenekoop, R.K., Schooneveld, M.J. van, Strom, T.M., Lith-Verhoeven, J.J. van, Lotery, A.J., Moll-Ramirez, N.G. van, Leroy, B.P., Born, L.I. van den, Hoyng, C.B., Cremers, F.P.M., Klaver, C.C., Thiadens, A.A.H.J., Hollander, A.I. den, Roosing, S., Nabuurs, S.B., Zekveld-Vroon, R.C., Collin, R.W.J., Baere, E. de, Koenekoop, R.K., Schooneveld, M.J. van, Strom, T.M., Lith-Verhoeven, J.J. van, Lotery, A.J., Moll-Ramirez, N.G. van, Leroy, B.P., Born, L.I. van den, Hoyng, C.B., Cremers, F.P.M., and Klaver, C.C.
- Abstract
Contains fulltext : 80462.pdf (publisher's version ) (Closed access), Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5'-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes.
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- 2009
36. Stress and innate immunity in carp: Corticosteroid receptors and pro-inflammatory cytokines
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Stolte, E.H., Nabuurs, S.B., Bury, N.R., Sturm, A., Flik, G., Savelkoul, H.F.J., Verburg-van Kemenade, B.M.L., Stolte, E.H., Nabuurs, S.B., Bury, N.R., Sturm, A., Flik, G., Savelkoul, H.F.J., and Verburg-van Kemenade, B.M.L.
- Abstract
Contains fulltext : 70948.pdf (postprint version ) (Open Access)
- Published
- 2008
37. Features of a twin-arginine signal peptide required for recognition by a Tat proofreading chaperone.
- Author
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Buchanan, G., Maillard, J., Nabuurs, S.B., Richardson, D.J., Palmer, T., Sargent, F., Buchanan, G., Maillard, J., Nabuurs, S.B., Richardson, D.J., Palmer, T., and Sargent, F.
- Abstract
Item does not contain fulltext, The twin-arginine translocation (Tat) system is a bacterial protein targeting pathway. Tat-targeted proteins display signal peptides containing a distinctive SRRxFLK 'twin-arginine' motif. The Escherichia coli trimethylamine N-oxide reductase (TorA) bears a bifunctional Tat signal peptide, which directs protein export and serves as a binding site for the TorD biosynthetic chaperone. Here, the physical interaction between TorD and the TorA signal peptide was investigated. A single substitution within the TorA signal peptide (L31Q) was sufficient to impair TorD binding. Screening of a random torD mutant library identified a variant TorD protein (Q7L) that displayed increased binding affinity for the TorA signal peptide.
- Published
- 2008
38. Basal laminar drusen caused by compound heterozygous variants in the CFH gene.
- Author
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Boon, C.J.F., Klevering, B.J., Hoyng, C.B., Zonneveld-Vrieling, M.N., Nabuurs, S.B., Blokland, E., Cremers, F.P.M., Hollander, A.I. den, Boon, C.J.F., Klevering, B.J., Hoyng, C.B., Zonneveld-Vrieling, M.N., Nabuurs, S.B., Blokland, E., Cremers, F.P.M., and Hollander, A.I. den
- Abstract
Contains fulltext : 70065.pdf (publisher's version ) (Closed access), Age-related macular degeneration (AMD) is a multifactorial disease that is strongly associated with the Tyr402His variant in the complement factor H (CFH) gene. Drusen are hallmark lesions of AMD and consist of focal-inflammatory and/or immune-mediated depositions of extracellular material at the interface of the retinal pigment epithelium (RPE) and the Bruch membrane. We evaluated the role of CFH in 30 probands with early-onset drusen and identified heterozygous nonsense, missense, and splice variants in five families. The affected individuals all carried the Tyr402His AMD risk variant on the other allele. This supports an autosomal-recessive disease model in which individuals who carry a CFH mutation on one allele and the Tyr402His variant on the other allele develop drusen. Our findings strongly suggest that monogenic inheritance of CFH variants can result in basal laminar drusen in young adults, and this can progress to maculopathy and severe vision loss later in life.
- Published
- 2008
39. Arts syndrome is caused by loss-of-function mutations in PRPS1.
- Author
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Brouwer, A.P.M. de, Williams, K.L., Duley, J.A., Kuilenburg, A.B.P. van, Nabuurs, S.B., Egmont-Peterson, M., Lugtenberg, D., Zoetekouw, L., Banning, M.J.G., Roeffen, M., Hamel, B.C.J., Weaving, L., Ouvrier, R.A., Donald, J.A., Wevers, R.A., Christodoulou, J., Bokhoven, J.H.L.M. van, Brouwer, A.P.M. de, Williams, K.L., Duley, J.A., Kuilenburg, A.B.P. van, Nabuurs, S.B., Egmont-Peterson, M., Lugtenberg, D., Zoetekouw, L., Banning, M.J.G., Roeffen, M., Hamel, B.C.J., Weaving, L., Ouvrier, R.A., Donald, J.A., Wevers, R.A., Christodoulou, J., and Bokhoven, J.H.L.M. van
- Abstract
Contains fulltext : 35096.pdf (publisher's version ) (Closed access), Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T-->C (p.L152P) in the Dutch family and c.398A-->C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway.
- Published
- 2007
40. A Flexible Approach to Induced Fit Docking
- Author
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Nabuurs, S.B., Wagener, M., Vlieg, J. de, Nabuurs, S.B., Wagener, M., and Vlieg, J. de
- Abstract
Item does not contain fulltext, We present Fleksy, a new approach to consider both ligand and receptor flexibility in small molecule docking. Pivotal to our method is the use of a receptor ensemble to describe protein flexibility. To construct these ensembles, we use a backbone-dependent rotamer library and implement the concept of interaction sampling. The latter allows the evaluation of different orientations of ambivalent interaction partners. The docking stage consists of an ensemble-based soft-docking experiment using FlexX-Ensemble, followed by an effective flexible receptor-ligand complex optimization using Yasara. Fleksy produces a set of receptor-ligand complexes ranked using a consensus scoring function combining docking scores and force field energies. Averaged over three cross-docking datasets, containing 35 different receptor-ligand complexes in total, Fleksy reproduces the observed binding mode within 2.0 A for 78% of the complexes. This compares favorably to the rigid receptor FlexX program, which on average reaches a success rate of 44% for these datasets.
- Published
- 2007
41. Basal laminar drusen caused by compound heterozygous variants in the CFH gene.
- Author
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Boon, C.J.F., Klevering, B.J., Hoyng, C.B., Zonneveld-Vrieling, M.N., Nabuurs, S.B., Blokland, E.A.W., Cremers, F.P.M., Hollander, A.I. den, Boon, C.J.F., Klevering, B.J., Hoyng, C.B., Zonneveld-Vrieling, M.N., Nabuurs, S.B., Blokland, E.A.W., Cremers, F.P.M., and Hollander, A.I. den
- Abstract
Contains fulltext : 35110.pdf (publisher's version ) (Closed access)
- Published
- 2007
42. ZNF674: A New Kruppel-Associated Box-Containing Zinc-Finger Gene Involved in Nonsyndromic X-Linked Mental Retardation.
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Lugtenberg, D., Yntema, H.G., Banning, M.J.G., Oudakker, A.R., Firth, H., Willatt, L., Raynaud, M., Kleefstra, T., Fryns, J.P., Ropers, H.H., Chelly, J., Moraine, C., Gecz, J., Reeuwijk, J. van, Nabuurs, S.B., Vries, L.B.A. de, Hamel, B.C.J., Brouwer, A.P.M. de, Bokhoven, J.H.L.M. van, Lugtenberg, D., Yntema, H.G., Banning, M.J.G., Oudakker, A.R., Firth, H., Willatt, L., Raynaud, M., Kleefstra, T., Fryns, J.P., Ropers, H.H., Chelly, J., Moraine, C., Gecz, J., Reeuwijk, J. van, Nabuurs, S.B., Vries, L.B.A. de, Hamel, B.C.J., Brouwer, A.P.M. de, and Bokhoven, J.H.L.M. van
- Abstract
Contains fulltext : 34765.pdf (publisher's version ) (Closed access), Array-based comparative genomic hybridization has proven to be successful in the identification of genetic defects in disorders involving mental retardation. Here, we studied a patient with learning disabilities, retinal dystrophy, and short stature. The family history was suggestive of an X-linked contiguous gene syndrome. Hybridization of full-coverage X-chromosomal bacterial artificial chromosome arrays revealed a deletion of ~1 Mb in Xp11.3, which harbors RP2, SLC9A7, CHST7, and two hypothetical zinc-finger genes, ZNF673 and ZNF674. These genes were analyzed in 28 families with nonsyndromic X-linked mental retardation (XLMR) that show linkage to Xp11.3; the analysis revealed a nonsense mutation, p.E118X, in the coding sequence of ZNF674 in one family. This mutation is predicted to result in a truncated protein containing the Kruppel-associated box domains but lacking the zinc-finger domains, which are crucial for DNA binding. We characterized the complete ZNF674 gene structure and subsequently tested an additional 306 patients with XLMR for mutations by direct sequencing. Two amino acid substitutions, p.T343M and p.P412L, were identified that were not found in unaffected individuals. The proline at position 412 is conserved between species and is predicted by molecular modeling to reduce the DNA-binding properties of ZNF674. The p.T343M transition is probably a polymorphism, because the homologous ZNF674 gene in chimpanzee has a methionine at that position. ZNF674 belongs to a cluster of seven highly related zinc-finger genes in Xp11, two of which (ZNF41 and ZNF81) were implicated previously in XLMR. Identification of ZNF674 as the third XLMR gene in this cluster may indicate a common role for these zinc-finger genes that is crucial to human cognitive functioning.
- Published
- 2006
43. The presence of multiple and differentially regulated interleukin-12p40 genes in bony fishes signifies an expansion of the vertebrate heterodimeric cytokine family
- Author
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Huising, M.O., Schijndel, J.E. van, Kruiswijk, C.P., Nabuurs, S.B., Savelkoul, H.F.J., Flik, G., Verburg-van Kemenade, B.M.L., Huising, M.O., Schijndel, J.E. van, Kruiswijk, C.P., Nabuurs, S.B., Savelkoul, H.F.J., Flik, G., and Verburg-van Kemenade, B.M.L.
- Abstract
Contains fulltext : 35175.pdf (publisher's version ) (Closed access), Interleukin-12 (IL-12) is the founding member of a rapidly growing family of heterodimeric cytokines. It consists of two subunits, designated p35 and p40 that together constitute a disulphide-linked heterodimeric cytokine. IL-12 is well known for its prominent role in both the early innate immune response and the skewing of the ensuing acquired immune response towards Th1. Here, we report the presence of IL-12p35 and three highly distinct IL-12p40 genes in common carp (Cyprinus carpio). The carp is a bony fish species genetically similar to the zebrafish, but its substantially larger body size facilitates immunological studies. A comparison of IL-12p35 genes of mammalian and non-mammalian species reveals the presence of a duplicated exon that is unique to the mammalian lineage. The organisation of the three carp IL-12p40 genes is similar to that of higher vertebrates. Phylogenetic analyses that include the p40-related subunits of other composite cytokines confirm the presence of three genuine IL-12p40 genes in carp and indicate that they are evolutionary ancient and possibly not restricted to bony fishes. The orthology of the different carp p40 subunits to mammalian IL-12p40 is further evident from the conservation of key residues involved in the formation of intra- and interchain disulphide bridges and the tight interlocking topology between p35 and p40. The expression of each of the carp IL-12p40 genes differs profoundly, constitutively as well as in response to in vitro stimulation of carp macrophages. Collectively, the presence of multiple and substantially different IL-12 genes signifies a considerable expansion of the vertebrate heterodimeric cytokine family.
- Published
- 2006
44. Increased leptin expression in common Carp (Cyprinus carpio) after food intake but not after fasting or feeding to satiation
- Author
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Huising, M.O., Geven, E.J.W., Kruiswijk, C.P., Nabuurs, S.B., Stolte, E.H., Spanings, F.A.T., Verburg-van Kemenade, B.M.L., Flik, G., Huising, M.O., Geven, E.J.W., Kruiswijk, C.P., Nabuurs, S.B., Stolte, E.H., Spanings, F.A.T., Verburg-van Kemenade, B.M.L., and Flik, G.
- Abstract
Contains fulltext : 35747.pdf (publisher's version ) (Open Access), Leptin is a key factor in the regulation of food intake and is an important factor in the pathophysiology of obesity. However, more than a decade after the discovery of leptin in mouse, information regarding leptin in any nonmammalian species is still scant. We report the identification of duplicate leptin genes in common carp (Cyprinus carpio). The unique gene structure, the conservation of both cysteines that form leptin's single disulfide bridge, and stable clustering in phylogenetic analyses substantiate the unambiguous orthology of mammalian and carp leptins, despite low amino acid identity. The liver is a major yet not the only site of leptin expression. However, neither 6 d nor 6 wk of fasting nor subsequent refeeding affected hepatic leptin expression, although the carp predictably shifted from carbohydrate to lipid metabolism. Animals that were fed to satiation grew twice as fast as controls; however, they did not show increased leptin expression at the termination of the study. Hepatic leptin expression did, however, display an acute and transient postprandial increase that follows the postprandial plasma glucose peak. In summary, leptin mRNA expression in carp changes acutely after food intake, but involvement of leptin in the long-term regulation of food intake and energy metabolism was not evident from fasting for days or weeks or long-term feeding to satiation. These are the first data on the regulation of leptin expression in any nonmammalian species.
- Published
- 2006
45. Negative constraints underlie the ErbB specificity of epidermal growth factor-like ligands
- Author
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Woning, S.P. van der, Rotterdam, W. van, Nabuurs, S.B., Venselaar, H., Jacobs-Oomen, S., Wingens, M., Vriend, G., Stortelers, C., Zoelen, E.J.J. van, Woning, S.P. van der, Rotterdam, W. van, Nabuurs, S.B., Venselaar, H., Jacobs-Oomen, S., Wingens, M., Vriend, G., Stortelers, C., and Zoelen, E.J.J. van
- Abstract
Contains fulltext : 35633.pdf (Publisher’s version ) (Open Access), Epidermal growth factor (EGF)-like growth factors bind their ErbB receptors in a highly selective manner, but the molecular basis for this specificity is poorly understood. We have previously shown that certain residues in human EGF (Ser(2)-Asp(3)) and TGFalpha (Glu(26)) are not essential for their binding to ErbB1 but prevent binding to ErbB3 and ErbB4. In the present study, we have used a phage display approach to affinity-optimize the C-terminal linear region of EGF-like growth factors for binding to each ErbB receptor and thereby shown that Arg(45) in EGF impairs binding to both ErbB3 and ErbB4. By omitting all these so-called negative constraints from EGF, we designed a ligand designated panerbin that binds ErbB1, ErbB3, and ErbB4 with similarly high affinity as their wild-type ligands. Homology models, based on the known crystal structure of TGFalpha-bound ErbB1, showed that panerbin is able to bind ErbB1, ErbB3, and ErbB4 in a highly similar manner with respect to position and number of interaction sites. Upon in silico introduction of the experimentally known negative constraints into panerbin, we found that Arg(45) induced local charge repulsion and Glu(26) induced steric hindrance in a receptor-specific manner, whereas Ser(2)-Asp(3) impaired binding due to a disordered conformation. Furthermore, radiolabeled panerbin was used to quantify the level of all three receptors on human breast cancer cells in a single radioreceptor assay. It is concluded that the ErbB specificity of EGF-like growth factors primarily results from the presence of a limited number of residues that impair the unintended interaction with other ErbB receptors.
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- 2006
46. On the quality of NMR structures. Methodology and tools for NMR data and structure validation
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Vriend, G., Vuister, G.W., Nabuurs, S.B., Vriend, G., Vuister, G.W., and Nabuurs, S.B.
- Abstract
RU Radboud Universiteit Nijmegen, 9 februari 2006, Promotores : Vriend, G., Vuister, G.W., Contains fulltext : 27386.pdf (publisher's version ) (Open Access)
- Published
- 2006
47. Definition of a new information-based per-residue quality parameter
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Nabuurs, S.B., Krieger, E., Spronk, C.A.E.M., Nederveen, A.J., Vriend, G., Vuister, G.W., Nabuurs, S.B., Krieger, E., Spronk, C.A.E.M., Nederveen, A.J., Vriend, G., and Vuister, G.W.
- Abstract
Item does not contain fulltext
- Published
- 2005
48. Solution structure of the second PDZ domain of the neuronal adaptor X11alpha and its interaction with the C-terminal peptide of the human copper chaperone for superoxide dismutase
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Duquesne, A.E., Ruijter, M., Brouwer, J., Drijfhout, J.W., Nabuurs, S.B., Spronk, C.A.E.M., Vuister, G.W., Ubbink, M.C., Canters, G.W., Duquesne, A.E., Ruijter, M., Brouwer, J., Drijfhout, J.W., Nabuurs, S.B., Spronk, C.A.E.M., Vuister, G.W., Ubbink, M.C., and Canters, G.W.
- Abstract
Item does not contain fulltext
- Published
- 2005
49. RECOORD: a Recalculated COORdinates Database of 500+ proteins from PDB using restraints from the BioMagResBank
- Author
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NMR-spectroscopie, NMR Spectroscopy 1, Dep Scheikunde, Nederveen, A.J., Doreleijers, J.F., Vranken, W., Miller, Z., Spronk, C.A.E.M., Nabuurs, S.B., Guntert, P., Livny, M., Markley, J.L., Nilges, M., Ulrich, E.L., Kaptein, R., Bonvin, A.M.J.J., NMR-spectroscopie, NMR Spectroscopy 1, Dep Scheikunde, Nederveen, A.J., Doreleijers, J.F., Vranken, W., Miller, Z., Spronk, C.A.E.M., Nabuurs, S.B., Guntert, P., Livny, M., Markley, J.L., Nilges, M., Ulrich, E.L., Kaptein, R., and Bonvin, A.M.J.J.
- Published
- 2005
50. Validation of protein structures derived by NMR spectroscopy
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Spronk, C.A.E.M., Nabuurs, S.B., Krieger, E., Vriend, G., Vuister, G.W., Spronk, C.A.E.M., Nabuurs, S.B., Krieger, E., Vriend, G., and Vuister, G.W.
- Abstract
Contains fulltext : 59100.pdf (publisher's version ) (Closed access)
- Published
- 2004
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