The DOI matches its Crossref record; 333 of the 333 references it cites were found in a registry or an index.
Controlling Allosteric Networks in Proteins
Abstract
Allosteric transition, defined as conformational changes induced by ligand binding, is one of the fundamental properties of proteins. Allostery has been observed and characterized in many proteins, and has been recently utilized to control protein function via regulation of protein activity. Here, we review the physical and evolutionary origin of protein allostery, as well as its importance to protein regulation, drug discovery, and biological processes in living systems. We describe recently developed approaches to identify allosteric pathways, connected sets of pairwise interactions that are responsible for propagation of conformational change from the ligand-binding site to a distal functional site. We then present experimental and computational protein engineering approaches for control of protein function by modulation of allosteric sites. As an example of application of these approaches, we describe a synergistic computational and experimental approach to rescue the cystic-fibrosis-associated protein cystic fibrosis transmembrane conductance regulator, which upon deletion of a single residue misfolds and causes disease. This example demonstrates the power of allosteric manipulation in proteins to both elucidate mechanisms of molecular function and to develop therapeutic strategies that rescue those functions. Allosteric control of proteins provides a tool to shine a light on the complex cascades of cellular processes and facilitate unprecedented interrogation of biological systems.
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“DNA alkylation drugs, as the first class of drugs targeting DNA, have been clinically used for nearly 70 years to treat cancers.468”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [468]
In the citing paper
“According to the ensemble model, first described in the 1980s (Cooper, 1984; Frauenfelder et al., 1988), the allosteric behavior of a macromolecular system arises from the properties of the native free-energy landscape of the system, and how this land-scape is remodeled by various “perturbations,” such as ligand binding, protonation, or interactions with other proteins (Dokholyan, 2016; Kern and Z”
From Allostery in Its Many Disguises: From Theory to Applications (2019) · cites this paper as Dokholyan, 2016
In the citing paper
“Unraveling the mechanistic underpinning of this behavior should therefore lead to improved understanding of how signaling events are relayed and regulated, and enable their modulation with promising pharmaceutical avenues for targeting human disease (Dokholyan, 2016).”
From Allostery in Its Many Disguises: From Theory to Applications (2019) · cites this paper as Dokholyan, 2016
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- 10.1016/j.str.2011.08.003 · DOI
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G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery
Zhang, M., Chen, T., Lu, X., Lan, X., Chen, K., & Lu, S. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01803-6 · Cited by 540
Allostery in Its Many Disguises: From Theory to Applications
Wodak, S. J., Paci, E., Dokholyan, N. V., Berezovsky, I. N., Horovitz, A., Li, J., Hilser, V. J., Bahar, I., Karanicolas, J., Stock, G., et al. (2019) · Structure · doi:10.1016/j.str.2019.01.003 · Cited by 404
Self-citationRecent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396
Designing allostery-inspired response in mechanical networks
Rocks, J. W., Pashine, N., Bischofberger, I., Goodrich, C. P., Liu, A. J., & Nagel, S. R. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612139114 · Cited by 204
“Although much work has focused on identifying, understanding, and controlling preexisting allosteric properties, the question of how to introduce new allosteric functions is relatively unexplored (21).”
BackgroundMapping allosteric communications within individual proteins
Wang, J., Jain, A., McDonald, L. R., Gambogi, C., Lee, A. L., & Dokholyan, N. V. (2020) · Nature Communications · doi:10.1038/s41467-020-17618-2 · Cited by 201
Self-citation
Metadata
- Authors
- Dokholyan, N. V.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Dokholyan, Nikolay V.
- Venue
- Chemical Reviews
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-02-19
- Volume
- 116
- Issue
- 11
- Pages
- 6463-6487
- ISSN
- 0009-2665 (ISSN-L)
- 1520-6890
- OpenAlex
- W2283716387
- Cited by
- 260
- References
- 333
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 24 · 2023: 48 · 2022: 23 · 2021: 31 · 2020: 27 · 2019: 28 · 2018: 21 · 2017: 18 · 2016: 7
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemical Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01 AI102732)
- National Institute of General Medical Sciences (5 R01 GM080742)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- protein allostery, allosteric networks, allosteric pathways, ligand-induced conformational change, protein regulation, protein engineering, cystic fibrosis transmembrane conductance regulator, CFTR, protein misfolding, drug discovery
- MeSH terms
- Allosteric Regulation, Allosteric Site, Humans, Ligands, Proteins, Cystic Fibrosis Transmembrane Conductance Regulator, Protein Structure, Quaternary, Focal Adhesion Protein-Tyrosine Kinases, Molecular Dynamics Simulation
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