Affinity Reagents that Target a Specific Inactive Form of Protein Kinases

被引：33

作者：

Ranjitkar, Pratistha ^{[1
]}

Brock, Amanda M. ^{[1
]}

Maly, Dustin J. ^{[1
]}

机构：

[1] Univ Washington, Dept Chem, Seattle, WA 98195 USA

来源：

CHEMISTRY & BIOLOGY | 2010年 / 17卷 / 02期

关键词：

STI-571; INHIBITION; INTERACTION MAP; C-SRC; ABL; ACTIVATION; POTENT; CONFORMATION; MECHANISM; BINDING; DISCOVERY;

D O I：

10.1016/j.chembiol.2010.01.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A number of small-molecule inhibitors have been developed that target the catalytic domains of protein kinases that are not in an active conformation. An inactive form that has been observed in several kinases is the DFG-out conformation. This conformation is characterized by an almost 180 degrees rotation of the conserved Asp-Phe-Gly (DFG) motif in the ATP-binding cleft relative to the active form. However, the sequence and structural determinants that allow a kinase to stably adopt the DFG-out conformation are not known. Here, we characterize a series of inhibitors based on a general pharmacophore for this inactive form. We demonstrate that modified versions of these inhibitors can be used to study the thermodynamics and kinetics of ligand binding to DFG-out-adopting kinases and for enriching these kinases from complex protein mixtures.

引用

页码：195 / 206

页数：12

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