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422 results on '"Siegal G"'

1. Increasing chemical space coverage by combining empirical and computational fragment screens

Author

Shoichet, Brian, Barelier, S, Eidam, O, Fish, I, Hollander, J, Figaroa, F, Nachane, R, Irwin, JJ, Shoichet, BK, and Siegal, G

Abstract

Most libraries for fragment-based drug discovery are restricted to 1,000-10,000 compounds, but over 500,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and

Published
2014

4. Fragment-derived modulators of an industrial β-glucosidase

Author

Makraki, E., Darby, J.F., Carneiro, M.G., Firth, J.D., Heyam, A., AB, E., O'Brien, P., Siegal, G., and Hubbard, R.E.

Abstract

A fragment screen of a library of 560 commercially available fragments using a kinetic assay identified a small molecule that increased the activity of the fungal glycoside hydrolase TrBgl2. An analogue by catalogue approach and detailed kinetic analysis identified improved compounds that behaved as nonessential activators with up to a 2-fold increase in maximum activation. The compounds did not activate the related bacterial glycoside hydrolase CcBglA demonstrating specificity. Interestingly, an analogue of the initial fragment inhibits both TrBgl2 and CcBglA, apparently through a mixed-model mechanism. Although it was not possible to determine crystal structures of activator binding to 55 kDa TrBgl2, solution NMR experiments demonstrated a specific binding site for the activator. A partial assignment of the NMR spectrum gave the identity of the amino acids at this site, allowing a model for TrBgl2 activation to be built. The activator binds at the entrance of the substrate binding site, generating a productive conformation for the enzyme-substrate complex.

Published
2020

5. Country Reports: the United Kingdom

Author

Zawati, MH, Chalmers, D, Dallari, SG, de Neiva Borba, M, Pinkesz, M, Joly, Y, Chen, H, Hartlev, M, Leitsalu, L, Soini, S, Rial-Sebbag, E, Hoppe, N, Garani-Papadatos, T, Vidalis, P, Srinivas, KR, Siegal, G, Negri, S, Hatanaka, R, Al-Hussaini, M, Al-Tabba', A, Motta-Murgía, L, Moran, LET, Hendriks, A, Nnamuchi, O, Isasi, R, Krekora-Zajac, D, Sadoun, E, Ho, C, Andanda, P, Lee, WB, Nicolás, P, Mattsson, T, Talanova, V, Dosch, A, Sprumont, D, Fan, C-T, Hung, T-H, Kaye, J, Phillips, A, Gowans, H, Shah, N, and Hazel, JW

Published
2020

10. Calcium extrusion is critical for cardiac morphogenesis and rhythm in embryonic zebrafish hearts

Author

Ebert, A.M., Hume, G.L., Warren, K.S., Cook, N.P., Burns, C.G., Mohideen, M.A., Siegal, G., Yelon, D., Fishman, M.C., and Garrity, D.M.

Subjects
Zebra fish -- Genetic aspects, Zebra fish -- Health aspects, Arrhythmia -- Research, Science and technology
Abstract

Calcium entry into myocytes drives contraction of the embryonic heart. To prepare for the next contraction, myocytes must extrude calcium from intracellular space via the [Na.sup.+]/[Ca.sup.2+] exchanger (NCX1) or sequester it into the sarcoplasmic reticulum, via the sarcoplasmic reticulum [Ca.sup.2+]-ATPase2 (SERCA2). In mammals, defective calcium extrusion correlates with increased intracellular calcium levels and may be relevant to heart failure and sarcoplasmic dysfunction in adults. We report here that mutation of the cardiac-specific NCX1 (NCX1h) gene causes embryonic lethal cardiac arrhythmia in zebrafish tremblor (tre) embryos. The tre ventricle is nearly silent, whereas the atrium manifests a variety of arrhythmias including fibrillation. Calcium extrusion defects in tre mutants correlate with severe disruptions in sarcomere assembly, whereas mutations in the L-type calcium channel that abort calcium entry do not produce this phenotype. Knockdown of SERCA2 activity by morpholino-mediated translational inhibition or pharmacological inhibition causes embryonic lethality due to defects in cardiac contractility and morphology but, in contrast to tre mutation, does not produce arrhythmia. Analysis of intracellular calcium levels indicates that homozygous tre embryos develop calcium overload, which may contribute to the degeneration of cardiac function in this mutant. Thus, the inhibition of NCX1h versus SERCA2 activity differentially affects the pathophysiology of rhythm in the developing heart and suggests that relative levels of NCX1 and SERCA2 function are essential for normal development. heart development | arrhythmia | sodium calcium exchanger | [Ca.sup.2+] -ATPase

Published
2005

19. Structure of the DNA-bound BRCA1 C-terminal Region from Human Replication Factor C p140 and Model of the Protein-DNA Complex

Author

Kobayashi, M., AB, E., Bonvin, A.M.J.J., Siegal, G., NMR Spectroscopy, Dep Scheikunde, Sub NMR Spectroscopy, NMR Spectroscopy, Dep Scheikunde, and Sub NMR Spectroscopy

Subjects
DNA Replication, Magnetic Resonance Spectroscopy, HMG-box, Protein Conformation, Molecular Sequence Data, Eukaryotic DNA replication, DNA and Chromosomes, Biology, Biochemistry, DNA replication factor CDT1, Replication factor C, Protein Interaction Mapping, Humans, Protein–DNA interaction, Amino Acid Sequence, Phosphorylation, Replication Protein C, Molecular Biology, Sequence Homology, Amino Acid, BRCA1 Protein, DNA replication, Computational Biology, DNA, Cell Biology, Molecular biology, Protein Structure, Tertiary, Cell biology, Kinetics, BRCT domain, biology.protein, Origin recognition complex, Algorithms
Abstract

BRCA1 C-terminal domain (BRCT)-containing proteins are found widely throughout the animal and bacteria kingdoms where they are exclusively involved in cell cycle regulation and DNA metabolism. Whereas most BRCT domains are involved in protein-protein interactions, a small subset has bona fide DNA binding activity. Here, we present the solution structure of the BRCT region of the large subunit of replication factor C bound to DNA and a model of the structure-specific complex with 5'-phosphorylated double-stranded DNA. The replication factor C BRCT domain possesses a large basic patch on one face, which includes residues that are structurally conserved and ligate the phosphate in phosphopeptide binding BRCT domains. An extra alpha-helix at the N terminus, which is required for DNA binding, inserts into the major groove and makes extensive contacts to the DNA backbone. The model of the protein-DNA complex suggests 5'-phosphate recognition by the BRCT domains of bacterial NAD(+)-dependent ligases and a nonclamp loading role for the replication factor C complex in DNA transactions.

Published
2010
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21. Solution structure of the 162 residue C-terminal domain of human elongation factor 1B gamma

Author

Vanwetswinkel, S., Kriek, J., Andersen, G.R., Guntert, P., Dijk, J., Canters, G.W., and Siegal, G.

Abstract

The multisubunit elongation factor 1 (eEF1) is required for the elongation step of eukaryotic protein synthesis. The eEF1 complex consists of four subunits: eEF1A, a G-protein that shuttles aminoacylated tRNAs to the ribosome; eEF1Balpha and eEF1Bbeta, two guanine nucleotide exchange factors, and eEF1Bgamma. Although its exact function remains unknown, this latter subunit is present in all eukaryotes. Recombinant human eEF1Bgamma has been purified and shown to consist of two independent domains. We have utilized high resolution NMR to determine the three-dimensional structure of the 19 kDa C-terminal fragment (domain 2). The structure consists of a five-stranded anti-parallel beta-sheet surrounded by alpha-helices and resembles a contact lens. Highly conserved residues are mainly located on the concave face, suggesting thereby that this side of the molecule might be involved in some biologically relevant interface(s). Although the isolated domain 2 appears to be mostly monomeric in solution, biochemical and structural data indicate a potential homodimer. The proposed dimer model can be further positioned within the quaternary arrangement of the whole eEF1 assembly.

Published
2003

25. LRRK2 secretion in exosomes is regulated by 14-3-3

Author

Fraser, K. B., primary, Moehle, M. S., additional, Daher, J. P. L., additional, Webber, P. J., additional, Williams, J. Y., additional, Stewart, C. A., additional, Yacoubian, T. A., additional, Cowell, R. M., additional, Dokland, T., additional, Ye, T., additional, Chen, D., additional, Siegal, G. P., additional, Galemmo, R. A., additional, Tsika, E., additional, Moore, D. J., additional, Standaert, D. G., additional, Kojima, K., additional, Mobley, J. A., additional, and West, A. B., additional

Published
2013
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30. EHRA Expert Consensus Statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy

Author

Padeletti, L., primary, Arnar, D. O., additional, Boncinelli, L., additional, Brachman, J., additional, Camm, J. A., additional, Daubert, J. C., additional, Hassam, S. K., additional, Deliens, L., additional, Glikson, M., additional, Hayes, D., additional, Israel, C., additional, Lampert, R., additional, Lobban, T., additional, Raatikainen, P., additional, Siegal, G., additional, and Vardas, P., additional

Published
2011
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38. ATPase

Author

Hilge, M., primary, Siegal, G., additional, Vuister, G.W., additional, Guentert, P., additional, Gloor, S.M., additional, and Abrahams, J.P., additional

Published
2003
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