Affiliation:
1. Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA.
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
Funder
National Institutes of Health
Publisher
American Association for the Advancement of Science (AAAS)
Cited by
157 articles.
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