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首页> 外文期刊>Acta crystallographica. Section D, Structural biology. >Crystal structures of apo and inhibitor-bound TGF beta R2 kinase domain: insights into TGF beta R isoform selectivity
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Crystal structures of apo and inhibitor-bound TGF beta R2 kinase domain: insights into TGF beta R isoform selectivity

机译：晶体结构apo和inhibitor-bound TGFβR2激酶结构域:洞察转化生长因子βR同种型选择性

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摘要

The cytokine TGF-beta 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-beta signals through two transmembrane serine/threonine kinase receptors: TGF beta R1 and TGF beta R2. Multiple structures of the TGF beta R1 kinase domain are known, but the structure of TGF beta R2 remains unreported. Wild-type TGF beta R2 kinase domain was refractory to crystallization, leading to the design of two mutated constructs: firstly, a TGF beta R1 chimeric protein with seven ATP-site residues mutated to their counterparts in TGF beta R2, and secondly, a reduction of surface entropy through mutation of six charged residues on the surface of the TGF beta R2 kinase domain to alanines. These yielded apo and inhibitor-bound crystals that diffracted to high resolution (<2 angstrom). Comparison of these structures with those of TGF beta R1 reveal shared ligand contacts as well as differences in the ATP-binding sites, suggesting strategies for the design of pan and selective TGF beta R inhibitors.
机译：细胞因子及调节的细胞活动,发挥了至关重要的作用开发、止血和生理学的疾病,包括癌症和纤维化。通过两个跨膜及信号丝氨酸/苏氨酸激酶受体:转化生长因子βR1转化生长因子β2。βR1激酶结构域是已知的,但是转化生长因子β2的结构仍未报告的。野生型转化生长因子βR2激酶结构域耐火材料结晶,导致的两个突变结构的设计:首先,TGFβR1与七ATP-site嵌合蛋白残基突变在TGF同行βR2,第二,减少表面熵通过六个带电残基的突变表面的转化生长因子βR2激酶结构域标明丙。inhibitor-bound晶体衍射高分辨率(< 2埃)。结构与转化生长因子βR1的揭示共享的配体接触以及差异磷酸腺苷网站,表明策略盘的设计和选择性转化生长因子βR抑制剂。

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