A Rotamer Relay Information System in the Epidermal Growth Factor Receptor-Drug Complexes Reveals Clues to New Paradigm in Protein Conformational Change

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62156489%3A43210%2F21%3A43920300" target="_blank" >RIV/62156489:43210/21:43920300 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216305:26620/21:PU142157

Výsledek na webu

<a href="https://doi.org/10.1016/j.csbj.2021.09.026" target="_blank" >https://doi.org/10.1016/j.csbj.2021.09.026</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.csbj.2021.09.026" target="_blank" >10.1016/j.csbj.2021.09.026</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A Rotamer Relay Information System in the Epidermal Growth Factor Receptor-Drug Complexes Reveals Clues to New Paradigm in Protein Conformational Change

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

A Rotamer Relay Information System in the Epidermal Growth Factor Receptor-Drug Complexes Reveals Clues to New Paradigm in Protein Conformational Change

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Computational and Structural Biotechnology Journal

ISSN

2001-0370

e-ISSN

—

Svazek periodika

19

Číslo periodika v rámci svazku

2021

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

12

Strana od-do

5443-5454

Kód UT WoS článku

000707933800011

EID výsledku v databázi Scopus

2-s2.0-85116521005