The ensemble nature of allostery
Open accessAbstract
Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.
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Allosteric modulators can change protein/substrate affinity in a highly predictable manner by stabilizing target proteins in inactive or active state, leading to desirable controllability.
“Allosteric modulators can change the protein/substrate affinity in a highly predictable manner by stabilizing target proteins in an inactive or active state, leading to desirable controllability.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [239]
The main parameters that determine allosteric behavior are the relative stabilities (or populations) of all accessible states, the timescales and energy barriers associated with transitions between states, and the binding affinities of ligands/effectors or conditions.
“The main parameters that determine the allosteric behavior are thus (1) the relative stabilities (or populations) of all the states accessible to the system including those corresponding to active and inactive conformations (with respect to ligand binding for instance), (2) the timescales and energy barriers associated with the transitions between states, and (3) the binding affinities of the lig”
From Allostery in Its Many Disguises: From Theory to Applications (2019) · cites this paper as Motlagh et al., 2014
The concept of allostery has evolved significantly since the first allosteric proteins were characterized.
“The concept of allostery has evolved significantly since the first allosteric proteins were characterized (Motlagh et al., 2014; Schueler-Furman and Wodak, 2016).”
From Allostery in Its Many Disguises: From Theory to Applications (2019) · cites this paper as Motlagh et al., 2014
Key to discovering allosteric sites is to consider proteins as ensembles of structures, capturing feasible but transient conformational states.
“Key to discovering allosteric sites is to consider proteins as ensembles of structures, capturing feasible, but transient, conformational states.262,263”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [262]
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Protein Allostery and Conformational Dynamics
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Impact of protein conformational diversity on AlphaFold predictions
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“According to this allosteric ensemble model, the flexibility of disorder allows complex allosteric behavior of IDRs in fine-tuning regulatory interactions (Hilser and Thompson, 2007; Motlagh et al., 2014).”
MethodASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks
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Allosteric conformational ensembles have unlimited capacity for integrating information
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Impact of protein conformational diversity on AlphaFold predictions
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- Authors
- Motlagh, H. N., Wrabl, J. O., Li, J., & Hilser, V. J.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Hilser, Vincent J.
- Venue
- Nature
- Published
- 2014-04-16
- Volume
- 508
- Issue
- 7496
- Pages
- 331-339
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4224315
- OpenAlex
- W1964439982
- Cited by
- 1,247
- References
- 110
- Citations by year
- 2026: 93 · 2025: 95 · 2024: 78 · 2023: 96 · 2022: 102 · 2021: 92 · 2020: 126 · 2019: 117 · 2018: 109 · 2017: 90 · 2016: 117 · 2015: 97 · 2014: 33
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM008403, GM63747, R01GM063747)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- allosteric regulation, allosteric mechanism, intrinsically disordered proteins, protein dynamics, conformational ensembles, enzyme regulation
- MeSH terms
- Allosteric Regulation, Allosteric Site, Hemoglobins, Ligands, Models, Molecular, Proteins, Thermodynamics, Protein Unfolding
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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