PDBsum entry 5mjb

Transferase

PDB id: 5mjb

Contents

Protein chains

278 a.a.

Ligands

7O3 ×2

SO4 ×5

Waters ×220

References listed in PDB file

Key reference

• Title: A chemical-Genetic approach to generate selective covalent inhibitors of protein kinases.
• Authors: A.Kung, M.Schimpl, A.Ekanayake, Y.C.Chen, R.Overman, C.Zhang.
• Ref.: ACS Chem Biol, 2017, 12, 1499-1503. [DOI no: 10.1021/acschembio.6b01083]
• PubMed id: 28459525

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.