Using ancient protein kinases to unravel a modern cancer drug's mechanism

被引：114

作者：

Wilson, C. ^{[1
,2
]}

Agafonov, R. V. ^{[1
,2
]}

Hoemberger, M. ^{[1
,2
]}

Kutter, S. ^{[1
,2
]}

Zorba, A. ^{[1
,2
]}

Halpin, J. ^{[1
,2
]}

Buosi, V. ^{[1
,2
]}

Otten, R. ^{[1
,2
]}

Waterman, D. ^{[1
,2
]}

Theobald, D. L. ^{[2
]}

Kern, D. ^{[1
,2
]}

机构：

[1] Brandeis Univ, Howard Hughes Med Inst, Waltham, MA 02452 USA

[2] Brandeis Univ, Dept Biochem, Waltham, MA 02452 USA

来源：

SCIENCE | 2015年 / 347卷 / 6224期

基金：

美国国家卫生研究院;

关键词：

C-SRC; RESURRECTED PROTEINS; CRYSTAL-STRUCTURE; TYROSINE KINASES; ABL KINASE; EVOLUTION; RECONSTRUCTION; CONFORMATION; INHIBITORS; IMATINIB;

D O I：

10.1126/science.aaa1823

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Macromolecular function is rooted in energy landscapes, where sequence determines not a single structure but an ensemble of conformations. Hence, evolution modifies a protein's function by altering its energy landscape. Here, we recreate the evolutionary pathway between two modern human oncogenes, Src and Abl, by reconstructing their common ancestors. Our evolutionary reconstruction combined with x-ray structures of the common ancestor and pre-steady-state kinetics reveals a detailed atomistic mechanism for selectivity of the successful cancer drug Gleevec. Gleevec affinity is gained during the evolutionary trajectory toward Abl and lost toward Src, primarily by shifting an induced-fit equilibrium that is also disrupted in the clinical T315I resistance mutation. This work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve.

引用

页码：882 / 886

页数：5

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