Download MendeleyCrystal structures of apo and inhibitor-bound TGF beta R2 kinase domain: insights into TGF beta R isoform selectivity.
Tebben, A.J., Ruzanov, M., Gao, M., Xie, D., Kiefer, S.E., Yan, C., Newitt, J.A., Zhang, L., Kim, K., Lu, H., Kopcho, L.M., Sheriff, S.(2016) Acta Crystallogr D Struct Biol 72: 658-674
- PubMed: 27139629
- DOI: https://doi.org/10.1107/S2059798316003624
- Primary Citation of Related Structures:
5E8S, 5E8T, 5E8U, 5E8V, 5E8W, 5E8X, 5E8Y, 5E8Z, 5E90, 5E91, 5E92 - PubMed 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.
Organizational Affiliation:
Molecular Structure and Design, Bristol-Myers Squibb R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.
