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Protein activity regulation by conformational entropy
Abstract
How the interplay between protein structure and internal dynamics regulates protein function is poorly understood. Often, ligand binding, post-translational modifications and mutations modify protein activity in a manner that is not possible to rationalize solely on the basis of structural data. It is likely that changes in the internal motions of proteins have a major role in regulating protein activity, but the nature of their contributions remains elusive, especially in quantitative terms. Here we show that changes in conformational entropy can determine whether protein-ligand interactions will occur, even among protein complexes with identical binding interfaces. We have used NMR spectroscopy to determine the changes in structure and internal dynamics that are elicited by the binding of DNA to several variants of the catabolite activator protein (CAP) that differentially populate the inactive and active DNA-binding domain states. We found that the CAP variants have markedly different affinities for DNA, despite the CAP−DNA-binding interfaces being essentially identical in the various complexes. Combined with thermodynamic data, the results show that conformational entropy changes can inhibit the binding of CAP variants that are structurally poised for optimal DNA binding or can stimulate the binding activity of CAP variants that only transiently populate the DNA-binding-domain active state. Collectively, the data show how changes in fast internal dynamics (conformational…
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“suggest that the observed changes in protein conformations and dynamics may alter protein activity [61].”
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Metadata
- Authors
- Tzeng, S.-R., & Kalodimos, C. G.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Kalodimos, Charalampos G.
- Venue
- Nature
- Published
- 2012-07-11
- Volume
- 488
- Issue
- 7410
- Pages
- 236-240
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2009239521
- Cited by
- 545
- References
- 30
- Citations by year
- 2026: 25 · 2025: 27 · 2024: 33 · 2023: 43 · 2022: 26 · 2021: 30 · 2020: 29 · 2019: 42 · 2018: 53 · 2017: 40 · 2016: 42 · 2015: 48 · 2014: 47 · 2013: 51 · 2012: 9
- FWCI
- 19.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Keywords
- CAP, protein-DNA interactions, conformational entropy, protein internal dynamics, protein conformational states, DNA-binding domain, protein structure-function relationship, protein variants, binding affinity, binding thermodynamics
- MeSH terms
- Binding Sites, Cyclic AMP Receptor Protein, DNA, Models, Molecular, Motion, Protein Binding, Time Factors, Protein Structure, Tertiary, Entropy, Nuclear Magnetic Resonance, Biomolecular
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