Two pathways mediate interdomain allosteric regulation in pin1
Open accessAbstract
Allostery is an essential means for regulating biomolecular functions and provides unique opportunities for drug design, yet our ability to elucidate allosteric mechanisms remains limited. Here, based on extensive molecular dynamics simulations, we present an atomistic picture of the pathways mediating the allosteric regulation of the PPIase domain of Pin1 by its WW domain. Two pathways jointly propagate the action of substrate-WW binding to produce closure and rigidification of three PPIase catalytic-site loops. One pathway preexists in the apo protein, but remains dormant until substrate-WW binding completes the second. The reduction in conformational entropy and preorganization of the catalytic-site loops observed here may explain why substrate-WW binding enhances ligand affinity and catalytic activity of the PPIase domain and suggest a combination drug therapy for Pin1-related diseases. Whereas the traditional view of allostery has emphasized conformational transition, our study identifies a distinct role of conformational dynamics in eliciting allostery.
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Even in a highly structured protein, "communication" between sites is likely mediated by multiple paths.
“Since even in a highly structured protein “communication” between sites is likely mediated by multiple paths (Guo et al., 2015; Taylor et al., 2016), the questions of whether a given path can be rigorously validated against experimental data, or whether its specific role can be rationalized, need to be critically evaluated.”
From Allostery in Its Many Disguises: From Theory to Applications (2019) · cites this paper as Guo et al., 2015
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Protein Allostery and Conformational Dynamics
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Self-citationAllostery in Its Many Disguises: From Theory to Applications
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- Authors
- Guo, J., Pang, X., & Zhou, H.-X.
- Affiliations
- Florida State University (US)
- Corresponding author
- Zhou, Huan-Xiang
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 23
- Issue
- 1
- Pages
- 237-247
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC4286514
- OpenAlex
- W1983871031
- Cited by
- 78
- References
- 50
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 10 · 2021: 3 · 2020: 7 · 2019: 9 · 2018: 10 · 2017: 3 · 2016: 13 · 2015: 8
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lanzhou University Institutional Repository (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM 58187, R01GM058187)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- Pin1, allosteric regulation, PPIase domain, WW domain, conformational entropy, conformational dynamics, ligand binding affinity, catalytic activity, drug design
- MeSH terms
- NIMA-Interacting Peptidylprolyl Isomerase, Allosteric Regulation, Binding Sites, Humans, Models, Molecular, Protein Binding, Drug Design, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Folding, Peptidylprolyl Isomerase, Amino Acid Substitution, Catalytic Domain, Protein Structure, Quaternary, Molecular Dynamics Simulation
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