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http://hdl.handle.net/20.500.11889/8022| Title: | Distinct dynamics and interaction patterns in H- and K-Ras oncogenic P-loop mutants | Authors: | Sayyed-Ahmad, Abdallah Prakash, Priyanka Gorfe, Alemayehu A. |
Keywords: | Ras proteins;Cancer - Chemotherapy;DNA - Transformations;Oncogenic mutations;Conformational transitions;Molecular dynamics | Issue Date: | 2017 | Abstract: | Despiteyearsofstudy,thestructuralordynamicalbasisforthedifferentialreactivityandoncogenicityofRasisoformsand mutantsremainsunclear.Inthisstudy,weinvestigatedtheeffectsofaminoacidvariationsonthestructureanddynamics ofwildtypeandoncogenicmutantsG12D,G12V,andG13DofH-andK-Rasproteins.Basedondatafromms-scalemoleculardynamicssimulations,weshowthattheoverallstructureoftheproteinsremainssimilarbutthereareimportantdifferencesindynamicsandinteractionnetworks.Weidentifieddifferencesinresidueinteractionpatternsaroundthecanonical switchanddistalloopregions,andpersistentsodiumionbindingneartheGTPparticularlyintheG13Dmutants.Our resultsalsosuggestthatdifferentRasvariantshavedistinctlocalstructuralfeaturesandinteractionswiththeGTP,variationsthathavethepotentialtoaffectGTPreleaseandhydrolysis.Furthermore,wefoundthatH-RasproteinsandparticularlytheG12VandG13DvariantsaresignificantlymoreflexiblethantheirK-Rascounterparts.Finally,whilemostofthe simulatedproteinssampledtheeffector-interactingstate2conformationalstate,G12VandG13DH-Rasadoptedanopen switchstate1conformationthatisdefectiveineffectorinteraction.ThesedifferenceshaveimplicationsforRasGTPase activity,effectororexchangefactorbinding,dimerizationandmembraneinteraction. | URI: | http://hdl.handle.net/20.500.11889/8022 |
| Appears in Collections: | Fulltext Publications |
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|---|---|---|---|---|
| Distinct dynamics and interaction patterns in H- and K-Ras oncogenic P-loop mutants.pdf | 1.35 MB | Adobe PDF | View/Open |
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