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9 results on '"van Beek, Lotte"'

1. Fragment-based Differential Targeting of PPI Stabilizer Interfaces

Author

Guillory, Xavier, Wolter, Madita, Leysen, Seppe, Neves, João Filipe, Kuusk, Ave, Genet, Sylvia, Somsen, Bente, Morrow, John Kenneth, Rivers, Emma, van Beek, Lotte, Patel, Joe, Goodnow, Robert, Schoenherr, Heike, Fuller, Nathan, Cao, Qing, Doveston, Richard G, Brunsveld, Luc, Arkin, Michelle R, Castaldi, Paola, Boyd, Helen, Landrieu, Isabelle, Chen, Hongming, and Ottmann, Christian

Subjects
Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 14-3-3 Proteins, Drug Design, Models, Molecular, Protein Binding, Protein Conformation, Small Molecule Libraries, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry
Abstract

Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This X-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.

Published
2020

2. Structural and biophysical characterisation of the repetitive regions from biofilm-mediating cell-wall anchored proteins

Author

van Beek, Lotte, Potts, Jennifer R., and Baumann, Christoph G.

Subjects
570
Abstract

Staphylococci and streptococci form microbial accumulations, defined as biofilms, on in-dwelling medical devices or damaged tissue. Biofilms are implicated in serious infections, such as infective endocarditis, with a mortality rate of 30%. Cell wall-anchored (CWA) proteins, containing a repetitive B region that putatively projects a functional A region from the bacterial surface, mediate biofilms, independent of other mechanisms. This highlights the need to better understand the mechanism of biofilm formation/accumulation by CWA proteins. Staphylococcus aureus surface protein C (SasC) mediates biofilm accumulation, but the structure and function of the B region, containing domains of unknown function (DUF1542), remains undetermined. SGO0707 from Streptococcus gordonii mediates surface adhesion putatively via its A domains; the function of the B region remains unknown. Here, the B regions of SasC and SGO0707 are biophysically characterised and their ability to form elongated stalks is assessed. Work presented in this thesis enables the redefinition of the domain boundaries for the repeats comprising the B region of SasC and renaming these as DUF1542 rigid extracellular surface structural (DRESS) domains. Tandem DRESS domains have tightly connected inter-domain interfaces that are essential for tandem domain stability and which mediate long-range stability. Importantly, DRESS domains form an extended, rigid rod and have remarkable mechanical stability, compared to other helical proteins. The B region of SGO0707 comprises SGO0707 high identity repeat tandem (SHIRT) domains with an extended tandem domain architecture, determined prior to this work. Here, SHIRT domains are shown to lack flexible loops and notably, the linker between SHIRT domains has limited flexibility, implying that tandem SHIRT domains have an extended, rod-like conformation in solution. Importantly, both domain architectures form a rigid rod, suggesting their ability to project the functional A region from the cell surface. Thus, staphylococci and streptococci have both evolved structurally distinct stalks-like CWA proteins to mediate biofilms.

Published
2019

4. Surface water retardation around single-chain polymeric nanoparticles: critical for catalytic function?

Author

Stals, Patrick JM, Cheng, Chi-Yuan, van Beek, Lotte, Wauters, Annelies C, Palmans, Anja RA, Han, Songi, and Meijer, EW

Subjects
Macromolecular and Materials Chemistry, Chemical Sciences, Nanotechnology, Bioengineering, Generic health relevance, Chemical sciences
Abstract

A library of water-soluble dynamic single-chain polymeric nanoparticles (SCPN) was prepared using a controlled radical polymerisation technique followed by the introduction of functional groups, including probes at targeted positions. The combined tools of electron paramagnetic resonance (EPR) and Overhauser dynamic nuclear polarization (ODNP) reveal that these SCPNs have structural and surface hydration properties resembling that of enzymes.

Published
2016

7. Surface water retardation around single-chain polymeric nanoparticles: critical for catalytic function?† †Electronic supplementary information (ESI) available: Synthetic procedures, CD- and IR spectra, additional information on ODNP and EPR spectra. See DOI: 10.1039/c5sc02319j

Author

Stals, Patrick J. M., Cheng, Chi-Yuan, van Beek, Lotte, Wauters, Annelies C., Palmans, Anja R. A., Han, Songi, and Meijer, E. W.

Subjects
Chemistry
Abstract

A library of water-soluble dynamic single-chain polymeric nanoparticles (SCPN) was prepared using a controlled radical polymerisation technique followed by the introduction of functional groups, including probes at targeted positions., A library of water-soluble dynamic single-chain polymeric nanoparticles (SCPN) was prepared using a controlled radical polymerisation technique followed by the introduction of functional groups, including probes at targeted positions. The combined tools of electron paramagnetic resonance (EPR) and Overhauser dynamic nuclear polarization (ODNP) reveal that these SCPNs have structural and surface hydration properties resembling that of enzymes.

Published
2015

9. Fragment-based Differential Targeting of PPI Stabilizer Interfaces

Author

Guillory, Xavier, Wolter, Madita, Leysen, Seppe, Neves, João Filipe, Kuusk, Ave, Genet, Sylvia, Somsen, Bente, Morrow, John Kenneth, Rivers, Emma, Van Beek, Lotte, Patel, Joe, Goodnow, Robert, Schoenherr, Heike, Fuller, Nathan, Cao, Qing, Doveston, Richard G., Brunsveld, Luc, Arkin, Michelle R., Castaldi, Paola, Boyd, Helen, Landrieu, Isabelle, Chen, Hongming, and Ottmann, Christian

Subjects
3. Good health
Abstract

Journal of medicinal chemistry 63(13), 6694 - 6707 (2020). doi:10.1021/acs.jmedchem.9b01942, Stabilization of protein–protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This X-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers., Published by ACS, Washington, DC

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