Detail publikace

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

HAMEDUH, T. MOKRÝ, M. MILLER, A. ADAM, V. HEGER, Z. HADDAD, Y.

Originální název

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

Typ

článek v časopise ve Web of Science, Jimp

Jazyk

angličtina

Originální abstrakt

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.

Klíčová slova

EGFR; NSCLC; Tumour resistance; Tyrosine kinase inhibitor; Rotamer; Protein structure; Protein folding

Autoři

HAMEDUH, T.; MOKRÝ, M.; MILLER, A.; ADAM, V.; HEGER, Z.; HADDAD, Y.

Vydáno

15. 11. 2021

Nakladatel

Elsevier

ISSN

2001-0370

Periodikum

Computational and Structural Biotechnology Journal

Ročník

19

Číslo

1

Stát

Švédské království

Strany od

5443

Strany do

5454

Strany počet

12

URL

https://doi.org/10.1016/j.csbj.2021.09.026

Plný text v Digitální knihovně

http://hdl.handle.net/11012/202968

BibTex

@article{BUT173209,
  author="Tareq {Hameduh} and Michal {Mokrý} and Andrew David {Miller} and Vojtěch {Adam} and Zbyněk {Heger} and Yazan Abdulmajeed Eyadh {Haddad}",
  title="A rotamer relay information system in the epidermal growth factor receptor-drug complexes reveals clues to new paradigm in protein conformational change",
  journal="Computational and Structural Biotechnology Journal",
  year="2021",
  volume="19",
  number="1",
  pages="5443--5454",
  doi="10.1016/j.csbj.2021.09.026",
  issn="2001-0370",
  url="https://doi.org/10.1016/j.csbj.2021.09.026"
}