5e90 Citations

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

Acta Crystallogr D Struct Biol 72 658-74 (2016)
Related entries: 5e8s, 5e8t, 5e8u, 5e8v, 5e8w, 5e8x, 5e8y, 5e8z, 5e91, 5e92

Cited: 14 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.

Reviews citing this publication (2)

  1. Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2. Williams E, Bullock AN. Bone 109 251-258 (2018)
  2. Structural biology of the TGFβ family. Goebel EJ, Hart KN, McCoy JC, Thompson TB. Exp Biol Med (Maywood) 244 1530-1546 (2019)

Articles citing this publication (12)