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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

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 struct...

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Autores principales: Hameduh, Tareq, Mokry, Michal, Miller, Andrew D., Adam, Vojtech, Heger, Zbynek, Haddad, Yazan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511715/
https://www.ncbi.nlm.nih.gov/pubmed/34667537
http://dx.doi.org/10.1016/j.csbj.2021.09.026
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author Hameduh, Tareq
Mokry, Michal
Miller, Andrew D.
Adam, Vojtech
Heger, Zbynek
Haddad, Yazan
author_facet Hameduh, Tareq
Mokry, Michal
Miller, Andrew D.
Adam, Vojtech
Heger, Zbynek
Haddad, Yazan
author_sort Hameduh, Tareq
collection PubMed
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.
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spelling pubmed-85117152021-10-18 A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change Hameduh, Tareq Mokry, Michal Miller, Andrew D. Adam, Vojtech Heger, Zbynek Haddad, Yazan Comput Struct Biotechnol J Research Article 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. Research Network of Computational and Structural Biotechnology 2021-09-27 /pmc/articles/PMC8511715/ /pubmed/34667537 http://dx.doi.org/10.1016/j.csbj.2021.09.026 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Hameduh, Tareq
Mokry, Michal
Miller, Andrew D.
Adam, Vojtech
Heger, Zbynek
Haddad, Yazan
A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change
title A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change
title_full A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change
title_fullStr A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change
title_full_unstemmed A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change
title_short A rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change
title_sort rotamer relay information system in the epidermal growth factor receptor–drug complexes reveals clues to new paradigm in protein conformational change
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511715/
https://www.ncbi.nlm.nih.gov/pubmed/34667537
http://dx.doi.org/10.1016/j.csbj.2021.09.026
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