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Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity.
- Source :
- Acta Crystallographica: Section D, Structural Biology; May2016, Vol. 72 Issue 5, p658-674, 16p
- Publication Year :
- 2016
-
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]
- Subjects :
- TRANSFORMING growth factors-beta
CRYSTAL structure
MEMBRANE proteins
Subjects
Details
- Language :
- English
- ISSN :
- 09074449
- Volume :
- 72
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- Acta Crystallographica: Section D, Structural Biology
- Publication Type :
- Academic Journal
- Accession number :
- 115377041
- Full Text :
- https://doi.org/10.1107/S2059798316003624