Conformational states dynamically populated by a kinase determine its function
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A moving target: Abl kinase is an important signaling protein that is dysregulated in leukemia and other cancers and is the target of inhibitors such as imatinib. Like other kinases, Abl kinase is dynamic, and regulating conformational dynamics is key to regulating activity. Xie et al. used nuclear magnetic resonance to show that the Abl kinase domain interconverts between one active and two inactive states. Imatinib stabilizes an inactive conformation, and several resistance mutations act by destabilizing this conformation. In a construct that includes the regulatory domain, depending on the relative arrangement of the kinase and regulatory domains, the kinase domain is stabilized in either the active state or one of the inhibited states. Understanding the conformational dynamics of kinases can be leveraged to design selective drugs. Science , this issue p. eabc2754
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A protein can exist in one conformation in its inactive state and another in its active state.
“However, a protein can exist in one conformation in its “inactive” state and another in its “active” state.53–56”
From AlphaFold 2: Why It Works and Its Implications for Understanding the Relationships of Protein Sequence, Structure, and Function (2021) · cites this paper as [56]
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Self-citationRennella, E., Huang, R., Vėlyvis, A., et al. (2015) · Journal of Biomolecular NMR · doi:10.1007/s10858-015-9974-z · Cited by 35 · see citing works
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Monneau, Y. R., Ishida, Y., Rossi, P., Saio, T., Tzeng, S., Inouye, M., & Kalodimos, C. G. (2016) · Journal of Biomolecular NMR · doi:10.1007/s10858-016-0041-1 · Cited by 31 · see citing works
Self-citationLipid-targeting pleckstrin homology domain turns its autoinhibitory face toward the TEC kinases
Amatya, N., Wales, T. E., Kwon, A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1907566116 · Cited by 26 · see citing works
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NMR Characterization of Information Flow and Allosteric Communities in the MAP Kinase p38γ
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Toolkit for NMR Studies of Methyl-Labeled Proteins
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Self-citationThe Ys and wherefores of protein kinase autoinhibition
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Skolnick, J., Gao, M., Zhou, H., & Singh, S. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c01114 · Cited by 251 · see citing works
High-throughput prediction of protein conformational distributions with subsampled AlphaFold2
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Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs
Nussinov, R., Zhang, M., Maloney, R., Liu, Y., Tsai, C.-J., & Jang, H. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167569 · Cited by 66 · see citing works
Representing structures of the multiple conformational states of proteins
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Breaking the conformational ensemble barrier: Ensemble structure modeling challenges in CASP15
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Protein multiple conformations prediction using multi-objective evolution algorithm
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Wang, B., Wang, C., Chen, J., Liu, D., Sun, C., Zhang, J., Zhang, K., & Li, H. (2026) · Nature Machine Intelligence · doi:10.1038/s42256-026-01198-9 · Cited by 5 · see citing works
- Authors
- Xie, T., Saleh, T., Rossi, P., & Kalodimos, C. G.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Kalodimos, Charalampos G.
- Venue
- Science
- Published
- 2020-10-09
- Volume
- 370
- Issue
- 6513
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7920495
- OpenAlex
- W3089408272
- Cited by
- 266
- References
- 100
- Citations by year
- 2026: 43 · 2025: 38 · 2024: 50 · 2023: 42 · 2022: 53 · 2021: 38 · 2020: 2
- FWCI
- 10.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R35 GM122462)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- 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
- Keywords
- c-Abl, kinase regulation, inactive kinase conformation, activation loop, DFG motif, gatekeeper residue, drug resistance, kinase inhibitors
- MeSH terms
- Imatinib Mesylate, Protein Domains, Humans, Mutation, Oligopeptides, Protein-Tyrosine Kinases, Genes, abl, Protein Structure, Secondary, Nuclear Magnetic Resonance, Biomolecular, Protein Kinase Inhibitors, Biocatalysis
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