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dc.contributor.authorMalhotra, Sonyen
dc.contributor.authorAlsulami, Alien
dc.contributor.authorHeiyun, Yangen
dc.contributor.authorOchoa, Bernardo Montanoen
dc.contributor.authorJubb, Harryen
dc.contributor.authorForbes, Simonen
dc.contributor.authorBlundell, Tomen
dc.date.accessioned2019-07-25T23:30:18Z
dc.date.available2019-07-25T23:30:18Z
dc.date.issued2019-01en
dc.identifier.issn1932-6203
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/294913
dc.description.abstractGenomics and genome screening are proving central to the study of cancer. However, a good appreciation of the protein structures coded by cancer genes is also invaluable, especially for the understanding of functions, for assessing ligandability of potential targets, and for designing new drugs. To complement the wealth of information on the genetics of cancer in COSMIC, the most comprehensive database for cancer somatic mutations available, structural information obtained experimentally has been brought together recently in COSMIC-3D. Even where structural information is available for a gene in the Cancer Gene Census, a list of genes in COSMIC with substantial evidence supporting their impacts in cancer, this information is quite often for a single domain in a larger protein or for a single protomer in a multiprotein assembly. Here, we show that over 60% of the genes included in the Cancer Gene Census are predicted to possess multiple domains. Many are also multicomponent and membrane-associated molecular assemblies, with mutations recorded in COSMIC affecting such assemblies. However, only 469 of the gene products have a structure represented in the PDB, and of these only 87 structures have 90-100% coverage over the sequence and 69 have less than 10% coverage. As a first step to bridging gaps in our knowledge in the many cases where individual protein structures and domains are lacking, we discuss our attempts of protein structure modelling using our pipeline and investigating the effects of mutations using two of our in-house methods (SDM2 and mCSM) and identifying potential driver mutations. This allows us to begin to understand the effects of mutations not only on protein stability but also on protein-protein, protein-ligand and protein-nucleic acid interactions. In addition, we consider ways to combine the structural information with the wealth of mutation data available in COSMIC. We discuss the impacts of COSMIC missense mutations on protein structure in order to identify and assess the molecular consequences of cancer-driving mutations.
dc.description.sponsorshipTLB acknowledges support through his Wellcome Trust Investigator Award 200814/Z/16/Z
dc.format.mediumElectronic-eCollectionen
dc.languageengen
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHumansen
dc.subjectNeoplasmsen
dc.subjectOncogene Proteinsen
dc.subjectLigandsen
dc.subjectComputational Biologyen
dc.subjectGenomicsen
dc.subjectProtein Conformationen
dc.subjectStructure-Activity Relationshipen
dc.subjectMutation, Missenseen
dc.subjectModels, Molecularen
dc.subjectDatabases, Geneticen
dc.subjectBiomarkers, Tumoren
dc.titleUnderstanding the impacts of missense mutations on structures and functions of human cancer-related genes: A preliminary computational analysis of the COSMIC Cancer Gene Census.en
dc.typeArticle
prism.issueIdentifier7en
prism.publicationDate2019en
prism.publicationNamePloS oneen
prism.startingPagee0219935
prism.volume14en
dc.identifier.doi10.17863/CAM.42001
dcterms.dateAccepted2019-07-03en
rioxxterms.versionofrecord10.1371/journal.pone.0219935en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-01en
dc.contributor.orcidMalhotra, Sony [0000-0002-3165-9081]
dc.contributor.orcidHeiyun, Yang [0000-0002-7670-1626]
dc.contributor.orcidJubb, Harry [0000-0001-6094-0975]
dc.contributor.orcidBlundell, Tom [0000-0002-2708-8992]
dc.identifier.eissn1932-6203
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (200814/Z/16/Z)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International