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

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dc.contributor.authorHameduh, Tareqcs
dc.contributor.authorMokrý, Michalcs
dc.contributor.authorMiller, Andrew Davidcs
dc.contributor.authorAdam, Vojtěchcs
dc.contributor.authorHeger, Zbyněkcs
dc.contributor.authorHaddad, Yazan Abdulmajeed Eyadhcs
dc.coverage.issue1cs
dc.coverage.volume19cs
dc.date.accessioned2021-11-23T15:56:19Z
dc.date.available2021-11-23T15:56:19Z
dc.date.issued2021-11-15cs
dc.description.abstractCancer 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.en
dc.formattextcs
dc.format.extent5443-5454cs
dc.format.mimetypeapplication/pdfcs
dc.identifier.citationComputational and Structural Biotechnology Journal. 2021, vol. 19, issue 1, p. 5443-5454.en
dc.identifier.doi10.1016/j.csbj.2021.09.026cs
dc.identifier.issn2001-0370cs
dc.identifier.other173209cs
dc.identifier.urihttp://hdl.handle.net/11012/202968
dc.language.isoencs
dc.publisherElseviercs
dc.relation"European Union (EU)" & "Horizon 2020"
dc.relation.ispartofComputational and Structural Biotechnology Journalcs
dc.relation.projectIdinfo:eu-repo/grantAgreement/EC/H2020/759585/EU//ToMeTuM
dc.relation.urihttps://doi.org/10.1016/j.csbj.2021.09.026cs
dc.rightsCreative Commons Attribution 4.0 Internationalcs
dc.rights.accessopenAccesscs
dc.rights.sherpahttp://www.sherpa.ac.uk/romeo/issn/2001-0370/cs
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/cs
dc.subjectEGFRen
dc.subjectNSCLCen
dc.subjectTumour resistanceen
dc.subjectTyrosine kinase inhibitoren
dc.subjectRotameren
dc.subjectProtein structureen
dc.subjectProtein foldingen
dc.titleA rotamer relay information system in the epidermal growth factor receptor-drug complexes reveals clues to new paradigm in protein conformational changeen
dc.type.driverarticleen
dc.type.statusPeer-revieweden
dc.type.versionpublishedVersionen
sync.item.dbidVAV-173209en
sync.item.dbtypeVAVen
sync.item.insts2021.11.23 16:56:19en
sync.item.modts2021.11.23 16:15:17en
thesis.grantorVysoké učení technické v Brně. Středoevropský technologický institut VUT. Chytré nanonástrojecs
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