5E8Y

TGF-BETA RECEPTOR TYPE 2 KINASE DOMAIN (E431A,R433A,E485A,K488A,R493A,R495A) IN COMPLEX WITH STAUROSPORINE

Summary for 5E8Y

• Entry DOI: 10.2210/pdb5e8y/pdb
• Related: 5E8S 5E8T 5E8U 5E8V 5E8W 5E8X 5E8Z 5E90 5E91 5E92
• Descriptor: TGF-beta receptor type-2, STAUROSPORINE (3 entities in total)
• Functional Keywords: kinase domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P37173
• Total number of polymer chains: 1
• Total formula weight: 36307.21

Authors

Sheriff, S. (deposition date: 2015-10-14, release date: 2016-05-11, Last modification date: 2023-09-27)

Primary citation

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.
Crystal structures of apo and inhibitor-bound TGF beta R2 kinase domain: insights into TGF beta R isoform selectivity.
Acta Crystallogr D Struct Biol, 72:658-674, 2016

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.

PubMed: 27139629
DOI: 10.1107/S2059798316003624

Experimental method

X-RAY DIFFRACTION (2.05 Å)