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BcL-xL Conformational Changes upon Fragment Binding Revealed by NMR
- Source :
- PLoS ONE, PLoS ONE, Public Library of Science, 2013, 8, pp.e64400. ⟨10.1371/journal.pone.0064400⟩, PLoS ONE, Vol 8, Iss 5, p e64400 (2013)
- Publication Year :
- 2013
- Publisher :
- Public Library of Science, 2013.
-
Abstract
- Protein-protein interactions represent difficult but increasingly important targets for the design of therapeutic compounds able to interfere with biological processes. Recently, fragment-based strategies have been proposed as attractive approaches for the elaboration of protein-protein surface inhibitors from fragment-like molecules. One major challenge in targeting protein-protein interactions is related to the structural adaptation of the protein surface upon molecular recognition. Methods capable of identifying subtle conformational changes of proteins upon fragment binding are therefore required at the early steps of the drug design process. In this report we present a fast NMR method able to probe subtle conformational changes upon fragment binding. The approach relies on the comparison of experimental fragment-induced Chemical Shift Perturbation (CSP) of amine protons to CSP simulated for a set of docked fragment poses, considering the ring-current effect from fragment binding. We illustrate the method by the retrospective analysis of the complex between the anti-apoptotic Bcl-xL protein and the fragment 4'-fluoro-[1,1'-biphenyl]-4-carboxylic acid that was previously shown to bind one of the Bcl-xL hot spots. The CSP-based approach shows that the protein undergoes a subtle conformational rearrangement upon interaction, for residues located in helices [Formula: see text]2, [Formula: see text]3 and the very beginning of [Formula: see text]5. Our observations are corroborated by residual dipolar coupling measurements performed on the free and fragment-bound forms of the Bcl-xL protein. These NMR-based results are in total agreement with previous molecular dynamic calculations that evidenced a high flexibility of Bcl-xL around the binding site. Here we show that CSP of protein amine protons are useful and reliable structural probes. Therefore, we propose to use CSP simulation to assess protein conformational changes upon ligand binding in the fragment-based drug design approach.
- Subjects :
- Carboxylic Acids
lcsh:Medicine
Plasma protein binding
01 natural sciences
Biochemistry
Physical Chemistry
Benzoates
Protein Structure, Secondary
Protein structure
Drug Discovery
Biomacromolecule-Ligand Interactions
lcsh:Science
0303 health sciences
Multidisciplinary
Chemistry
Physics
Applied Chemistry
Protein fragment library
Biphenyl compound
Molecular Docking Simulation
Organic Acids
Thermodynamics
Research Article
Protein Binding
[PHYS.NUCL]Physics [physics]/Nuclear Theory [nucl-th]
Surface Properties
Nuclear Magnetic Resonance
Biophysics
bcl-X Protein
010402 general chemistry
Protein–protein interaction
03 medical and health sciences
Molecular recognition
[CHIM.ANAL]Chemical Sciences/Analytical chemistry
Chemical Biology
Humans
Binding site
Protein Structure, Quaternary
Biology
Nuclear Magnetic Resonance, Biomolecular
030304 developmental biology
Binding Sites
lcsh:R
Organic Chemistry
Biphenyl Compounds
Proteins
0104 chemical sciences
Chemical Properties
Residual dipolar coupling
Structural Homology, Protein
lcsh:Q
Medicinal Chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 8
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....8dffaba00eb0fa6ba9484af923121330