蛋白激酶结构域
激酶
转化生长因子
基因亚型
化学
生物
细胞生物学
生物化学
分子生物学
基因
突变体
作者
Andrew J. Tebben,Maxim Ruzanov,Mian Gao,Dan Xie,Susan E. Kiefer,Chunhong Yan,John A. Newitt,Liping Zhang,Kyoung Kim,Hao Lü,Lisa M. Kopcho,S. Sheriff
出处
期刊:Acta Crystallographica Section D-biological Crystallography
[International Union of Crystallography]
日期:2016-04-26
卷期号:72 (5): 658-674
被引量:21
标识
DOI:10.1107/s2059798316003624
摘要
The cytokine TGF-β modulates a number of cellular activities and plays a critical role in development, hemostasis and physiology, as well as in diseases including cancer and fibrosis. TGF-β signals through two transmembrane serine/threonine kinase receptors: TGFβR1 and TGFβR2. Multiple structures of the TGFβR1 kinase domain are known, but the structure of TGFβR2 remains unreported. Wild-type TGFβR2 kinase domain was refractory to crystallization, leading to the design of two mutated constructs: firstly, a TGFβR1 chimeric protein with seven ATP-site residues mutated to their counterparts in TGFβR2, and secondly, a reduction of surface entropy through mutation of six charged residues on the surface of the TGFβR2 kinase domain to alanines. These yielded apo and inhibitor-bound crystals that diffracted to high resolution (<2 Å). Comparison of these structures with those of TGFβR1 reveal shared ligand contacts as well as differences in the ATP-binding sites, suggesting strategies for the design of pan and selective TGFβR inhibitors.
科研通智能强力驱动
Strongly Powered by AbleSci AI