research papers
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.
Keywords: TGFβR2 kinase domain; apo and inhibitor-bound structures; TGFβR1 and TGFβR2 isoform selectivity.
Supporting information
Portable Document Format (PDF) file https://doi.org/10.1107/S2059798316003624/dw5158sup1.pdf |
PDB references: apo TGFβR1-WT, 5e8s; apo TGFβR1-T204D, 5e8t; apo TGFβR1-8M, 5e8u; apo TGFβR2-6M, 5e8v; TGFβR1-T204D, complex with staurosporine, 5e8w; TGFβR1-8M, complex with staurosporine, 5e8x; TGFβR2-6M, complex with staurosporine, 5e8y; TGFβR1-T204D, complex with compound 1, 5e8z; TGFβR1-8M, complex with compound 1, 5e90; TGFβR2-6M, complex with compound 1, 5e91; TGFβR2-6M, complex with AMPPNP, 5e92