A rotamer relay information system in the epidermal growth factor receptor-drug complexes reveals clues to new paradigm in protein conformational change.

Tareq Hameduh,Vojtech Adam,Yazan Haddad,Zbynek Heger,Michal Mokry,Andrew D Miller

doi:10.1016/j.csbj.2021.09.026

Abstract

Cancer cells can escape the effects of chemotherapy through mutations and upregulation of a tyrosine kinase protein called the epidermal growth factor receptor (EGFR). In the past two decades, four generations of tyrosine kinase inhibitors targeting EGFR have been developed. Using comparative structure analysis of 116 EGFR-drug complex crystal structures, cluster analysis produces two clans of 73 and 43 structures, respectively. The first clan of 73 structures is larger and is comprised mostly of the C-helix-IN conformation while the second clan of 43 structures correlates with the C-helix-OUT conformation. A deep rotamer analysis identifies 43 residues (18%) of the total of 237 residues spanning the kinase structures under investigation with significant rotamer variations between the C-helix-IN and C-helix-OUT clans. The locations of these rotamer variations take on the appearance of side chain conformational relays extending out from points of EGFR mutation to different regions of the EGFR kinase. Accordingly, we propose that key EGFR mutations act singly or together to induce drug resistant conformational changes in EGFR that are communicated via these side chain conformational relays. Accordingly, these side chain conformational relays appear to play a significant role in the development of tumour resistance. This phenomenon also suggests a new paradigm in protein conformational change that is mediated by supportive relays of rotamers on the protein surface, rather than through conventional backbone movements.

Highlights

Epidermal growth factor receptor (EGFR) protein was discovered in the late 1970s, and to this day it remains a primary target for anticancer therapy [1,2]
The C797S mutation could act to trigger the relay of a ‘‘flow of information” from rotamer to rotamer to desensitize EGFR kinase to tyrosine kinase inhibitors (TKIs)
We would suggest that the V948R mutation could act to trigger the relay of a ‘‘flow of information” from rotamer to rotamer to desensitize EGFR kinase to TKIs

Summary

Introduction

Epidermal growth factor receptor (EGFR) protein was discovered in the late 1970s, and to this day it remains a primary target for anticancer therapy [1,2]. Mutations and upregulation of EGFR are known mechanisms of both oncogenesis and therapeutic resistance. Active EGFR mutants escape the effects of chemotherapy via continuous proliferation and evasion of apoptosis, especially in the case of non-small cell carcinoma of the lung (NSCLC) [3]. EGFR is a member of the receptor tyrosine kinases (RTKs) cell. The primary function of EGFR is to mediate signals for differentiation, motility, and apoptosis [6]. Any irregular EGFR behaviour can become pro-oncogenic [7]. Pro-oncogenic mutations in EGFRs are widespread and linked to tumour overgrowth and resistance to chemotherapy [8]

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