Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity

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• 作者：Andrew J. Tebben ; Maxim Ruzanov ; Mian Gao ; Dianlin Xie ; Susan E. Kiefer ; Chunhong Yan ; John A. Newitt ; Liping Zhang ; Kyoung Kim ; Hao Lu ; Lisa M. Kopcho and Steven Sheriff
• 关键词：TGF&beta ; R2 kinase domain ; apo and inhibitor-bound structures ; TGF&beta ; R1 and TGF&beta ; R2 isoform selectivity
• 刊名：Acta Crystallographica Section D
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：72
• 期：5
• 页码：658-674
• 全文大小：1931K
• ISSN：1399-0047

文摘

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.