2020
NMR in integrated biophysical drug discovery for RAS: past, present, and future
Marshall C, KleinJan F, Gebregiworgis T, Lee K, Fang Z, Eves B, Liu N, Gasmi-Seabrook G, Enomoto M, Ikura M. NMR in integrated biophysical drug discovery for RAS: past, present, and future. Journal Of Biomolecular NMR 2020, 74: 531-554. PMID: 32804298, DOI: 10.1007/s10858-020-00338-6.Peer-Reviewed Original ResearchConceptsGTPase domainProper membrane localizationMultiple signaling cascadesOncogenic Ras mutationsKey downstream effectorDrug discoveryGTPase cycleMembrane localizationRAS proteinsGTP hydrolysisConformational selectionRAS signalingDownstream effectorsSignaling cascadesLipid modificationG12C mutantUpstream regulatorBiophysical approachesSmall proteinsRAS oncogenesDruggable pocketHuman cancersCell growthCovalent inhibitorsPeptidyl inhibitorsMultivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane
Fang Z, Lee K, Huo K, Gasmi-Seabrook G, Zheng L, Moghal N, Tsao M, Ikura M, Marshall C. Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 12101-12108. PMID: 32414921, PMCID: PMC7275734, DOI: 10.1073/pnas.1914076117.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesCell MembraneCysteineHumansMolecular Dynamics SimulationMutationProtein BindingProtein ConformationProtein DomainsProto-Oncogene Proteins c-rafProto-Oncogene Proteins p21(ras)ConceptsRas-binding domainCysteine-rich domainC-terminusΑ4-α5Transient electrostatic interactionsLipid-binding siteCancer-associated mutationsMembrane interfaceKRAS dimerizationMembrane anchoringMembrane associationKinase domainRaf kinaseMembrane complexPlasma membraneStructural insightsKinase activityMAPK signalingTerminusComplex formationMembraneDynamic interactionDynamic pictureComplexesDomainTwo Distinct Structures of Membrane‐Associated Homodimers of GTP‐ and GDP‐Bound KRAS4B Revealed by Paramagnetic Relaxation Enhancement
Lee K, Fang Z, Enomoto M, Gasmi‐Seabrook G, Zheng L, Koide S, Ikura M, Marshall C. Two Distinct Structures of Membrane‐Associated Homodimers of GTP‐ and GDP‐Bound KRAS4B Revealed by Paramagnetic Relaxation Enhancement. Angewandte Chemie International Edition 2020, 59: 11037-11045. PMID: 32227412, PMCID: PMC7395670, DOI: 10.1002/anie.202001758.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesDimerizationGuanosine DiphosphateGuanosine TriphosphateHumansMagnetic Resonance SpectroscopyMolecular Dynamics SimulationProto-Oncogene Proteins p21(ras)ConceptsKRAS dimerizationParamagnetic relaxation enhancement NMR spectroscopyStructural basisΑ4-α5 interfaceEffector-binding siteParamagnetic relaxation enhancementActive GTPRaf activationSmall GTPasesDistinct structuresRaf kinaseGTPDimerizationRelaxation enhancementKRAS4bGTPasesR135E168ActivationKinaseProtomersHomodimerNanodiscsNMR spectroscopyMembrane
2018
Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site
Fang Z, Marshall C, Nishikawa T, Gossert A, Jansen J, Jahnke W, Ikura M. Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site. Cell Chemical Biology 2018, 25: 1327-1336.e4. PMID: 30122370, DOI: 10.1016/j.chembiol.2018.07.009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsDrug DiscoveryEnzyme InhibitorsHumansIndolesLipid BilayersModels, MolecularPiperidinesProto-Oncogene Proteins p21(ras)