Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases 英文参考文献.docVIP

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Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases 英文参考文献.doc

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Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases 英文参考文献

SequenceandStructureSignaturesofCancerMutation HotspotsinProteinKinases AnshumanDixit1,2,LinYi1,RagulGowthaman1,AliTorkamani3,NicholasJ.Schork3,GennadyM. Verkhivker1,2,4 * 1GraduateProgramforBioinformatics,CenterforBioinformatics,TheUniversityofKansas,Lawrence,Kansas,UnitedStatesofAmerica,2DepartmentofPharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas, United States of America, 3Scripps Genomic Medicine, Department of Molecular and ExperimentalMedicine,Scripps Health and TheScrippsResearchInstitute,LaJolla, California, United States of America, 4Department of Pharmacology, University of CaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica Abstract Protein kinases are the most common protein domains implicated in cancer, where somatically acquired mutations are known to be functionally linked to a variety of cancers. Resequencing studies of protein kinase coding regions have emphasizedtheimportanceofsequenceandstructuredeterminantsofcancer-causingkinasemutationsinunderstanding of the mutation-dependent activation process. We have developed an integrated bioinformatics resource, which consolidated and mapped all currently available information on genetic modifications in protein kinase genes with sequence,structureandfunctionaldata.Theintegrationofdiversedatatypesprovidedaconvenientframeworkforkinome- wide study of sequence-based and structure-based signatures of cancer mutations. The database-driven analysis has revealed a differential enrichment of SNPs categories in functional regions of the kinase domain, demonstrating that a significant number of cancer mutations could fall at structurally equivalent positions (mutational hotspots) within the catalyticcore.Wehavealsofoundthatstructurallyconservedmutationalhotspotscanbesharedbymultiplekinasegenes andareoftenenrichedbycancerdrivermutationswithhighoncogenicactivity.Structuralmodelingandenergeticanalysis ofthemutationalhotspotshavesuggestedacommonmolecularmechanismof