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

Tebben AJ, Ruzanov M, Gao M, Xie D, Kiefer SE, Yan C, Newitt JA, Zhang L, Kim K, Lu H, Kopcho LM, Sheriff S
Acta Crystallogr D Struct Biol 72 658-74 (2016)
Related entries: 5e8s, 5e8t, 5e8u, 5e8v, 5e8w, 5e8x, 5e8z, 5e90, 5e91, 5e92

Cited: 15 times
EuropePMC logo PMID: 27139629

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.

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