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BIO DESIGN

pISSN 2288-6982
eISSN 2288-7105

Article

Article

Article

BioDesign 2021; 9(1): 14-18

Published online March 30, 2021

https://doi.org/10.34184/kssb.2021.9.1.14

© Korean Society for Structural Biology

Structural mechanism of inhibitor-resistance by ERK2 mutations

Yun Seong Park, Myeongbin Kim and Seong Eon Ryu*

Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea

Correspondence to: ryuse@hanyang.ac.kr
These authors contributed equally to this work.

Received: February 22, 2021; Revised: March 16, 2021; Accepted: March 16, 2021

Abstract

Extracellular signal-regulated kinase (ERK) is a serine-threonine kinase that is involved in the regulation of cellular signals. ERK inhibitors have been developed to treat cancers with B-Raf proto-oncogene mutations. However, the use of these inhibitors in disease settings induces ERK mutations resistant to the inhibitors, which poses major difficulties in effective cancer treatment. Here, we present the crystal structures of the ERK Y36H and G37C mutants that occur in cancer cells resistant to ERK inhibitors. The structures revealed mechanisms by which these mutations confer inhibitor-resistance to ERK. The Y36H mutant structure revealed a resistance mechanism that involves rotations of the His36 residue in the Gly-rich loop and the Tyr64 residue in the helix C, which blocks the entrance of inhibitors to the ATP-binding pocket. Furthermore, the G37C mutant structure exhibited that the mutation-induced rigidity in dihedral angles plays a major role in inducing inhibitor-resistance. Detailed structural information on the resistance mechanism suggests strategy for designing of novel inhibitors that can circumvent mutation-induced inhibitor resistance.