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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

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • 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

  • 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