Cited by 266Protein Kinase Regulation and GTPase SignalingProtein Structure and DynamicsReceptor Mechanisms and Signaling

Conformational states dynamically populated by a kinase determine its function

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Xie, Tao, Saleh, Tamjeed, Rossi, Paolo, Kalodimos, Charalampos G.·2020·Science

Abstract

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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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
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
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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