蛋白激酶结构域
原癌基因酪氨酸蛋白激酶Src
激酶
生物
抗药性
细胞生物学
生物化学
计算生物学
化学
突变体
遗传学
基因
作者
Sujata Chakraborty,Ethan Ahler,Jessica Simon,Linglan Fang,Zachary E. Potter,Katherine A. Sitko,Jason J. Stephany,Miklós Guttman,Douglas M. Fowler,Dustin J. Maly
标识
DOI:10.1016/j.chembiol.2023.08.005
摘要
Summary
Kinase inhibitors are effective cancer therapies, but resistance often limits clinical efficacy. Despite the cataloging of numerous resistance mutations, our understanding of kinase inhibitor resistance is still incomplete. Here, we comprehensively profiled the resistance of ∼3,500 Src tyrosine kinase mutants to four different ATP-competitive inhibitors. We found that ATP-competitive inhibitor resistance mutations are distributed throughout Src's catalytic domain. In addition to inhibitor contact residues, residues that participate in regulating Src's phosphotransferase activity were prone to the development of resistance. Unexpectedly, we found that a resistance-prone cluster of residues located on the top face of the N-terminal lobe of Src's catalytic domain contributes to autoinhibition by reducing catalytic domain dynamics, and mutations in this cluster led to resistance by lowering inhibitor affinity and promoting kinase hyperactivation. Together, our studies demonstrate how drug resistance profiling can be used to define potential resistance pathways and uncover new mechanisms of kinase regulation.
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