1. Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity.
- Author
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Tebben, Andrew J., Ruzanov, Maxim, Gao, Mian, Xie, Dianlin, Kiefer, Susan E., Yan, Chunhong, Newitt, John A., Zhang, Liping, Kim, Kyoung, Lu, Hao, Kopcho, Lisa M., and Sheriff, Steven
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TRANSFORMING growth factors-beta ,CRYSTAL structure ,MEMBRANE proteins - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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