5MJB

Kinase domain of human EphB1, G703C mutant, covalently bound to a quinazoline-based inhibitor

Summary for 5MJB

• Entry DOI: 10.2210/pdb5mjb/pdb
• Descriptor: Ephrin type-B receptor 1, 2-chloranyl-~{N}-[4-[(2-chloranyl-5-oxidanyl-phenyl)amino]quinazolin-7-yl]ethanamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: receptor tyrosine kinase, kinase domain, inhibitor, covalent, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P54762
• Total number of polymer chains: 2
• Total formula weight: 71014.12

Authors

Kung, A.,Schimpl, M.,Chen, Y.-C.,Overman, R.C.,Zhang, C. (deposition date: 2016-11-30, release date: 2017-05-17, Last modification date: 2024-11-06)

Primary citation

Kung, A.,Schimpl, M.,Ekanayake, A.,Chen, Y.C.,Overman, R.,Zhang, C.
A Chemical-Genetic Approach to Generate Selective Covalent Inhibitors of Protein Kinases.
ACS Chem. Biol., 12:1499-1503, 2017

PubMed Abstract: Although a previously developed bump-hole approach has proven powerful in generating specific inhibitors for mapping functions of protein kinases, its application is limited by the intolerance of the large-to-small mutation by certain kinases and the inability to control two kinases separately in the same cells. Herein, we describe the development of an alternative chemical-genetic approach to overcome these limitations. Our approach features the use of an engineered cysteine residue at a particular position as a reactive feature to sensitize a kinase of interest to selective covalent blockade by electrophilic inhibitors and is thus termed the Ele-Cys approach. We successfully applied the Ele-Cys approach to identify selective covalent inhibitors of a receptor tyrosine kinase EphB1 and solved cocrystal structures to determine the mode of covalent binding. Importantly, the Ele-Cys and bump-hole approaches afforded orthogonal inhibition of two distinct kinases in the cell, opening the door to their combined use in the study of multikinase signaling pathways.

PubMed: 28459525
DOI: 10.1021/acschembio.6b01083

Experimental method

X-RAY DIFFRACTION (2.23 Å)