A Rotamer Relay Information System in the Epidermal Growth Factor Receptor-Drug Complexes Reveals Clues to New Paradigm in Protein Conformational Change
The result's identifiers
Result code in 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>
Alternative codes found
RIV/00216305:26620/21:PU142157
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
A Rotamer Relay Information System in the Epidermal Growth Factor Receptor-Drug Complexes Reveals Clues to New Paradigm in Protein Conformational Change
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Computational and Structural Biotechnology Journal
ISSN
2001-0370
e-ISSN
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Volume of the periodical
19
Issue of the periodical within the volume
2021
Country of publishing house
NL - THE KINGDOM OF THE NETHERLANDS
Number of pages
12
Pages from-to
5443-5454
UT code for WoS article
000707933800011
EID of the result in the Scopus database
2-s2.0-85116521005