2020
Multivalent 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 ResearchConceptsRas-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 2020, 132: 11130-11138. DOI: 10.1002/ange.202001758.Peer-Reviewed Original ResearchKRAS dimerizationParamagnetic relaxation enhancement NMR spectroscopyStructural basisΑ4-α5 interfaceEffector-binding siteParamagnetic relaxation enhancementActive GTPRaf activationSmall GTPasesRaf kinaseDistinct structuresGTPDimerizationRelaxation enhancementKRAS4bGTPasesE168R135ActivationKinaseProtomersHomodimerNanodiscsNMR spectroscopyTwo 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 ResearchConceptsKRAS dimerizationParamagnetic relaxation enhancement NMR spectroscopyStructural basisΑ4-α5 interfaceEffector-binding siteParamagnetic relaxation enhancementActive GTPRaf activationSmall GTPasesDistinct structuresRaf kinaseGTPDimerizationRelaxation enhancementKRAS4bGTPasesR135E168ActivationKinaseProtomersHomodimerNanodiscsNMR spectroscopyMembrane
2018
Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling
Rukhlenko OS, Khorsand F, Krstic A, Rozanc J, Alexopoulos LG, Rauch N, Erickson KE, Hlavacek WS, Posner RG, Gómez-Coca S, Rosta E, Fitzgibbon C, Matallanas D, Rauch J, Kolch W, Kholodenko BN. Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. Cell Systems 2018, 7: 161-179.e14. PMID: 30007540, PMCID: PMC6149545, DOI: 10.1016/j.cels.2018.06.002.Peer-Reviewed Original ResearchConceptsOncogenic RasERK signalingRas/ERK pathwayRAF inhibitorsOncogenic Ras signalingMEK/ERKStructure-based modelingRAF inhibitor resistanceRAS mutant tumorsRas signalingPosttranslational modificationsRaf kinaseERK activityRAF dimerizationDrug-protein interactionsERK pathwayMultiple inhibitorsColony formationSignalingMutant NRASCell proliferationDrug designParadoxical activationInhibitor resistanceMechanistic dynamic model
2015
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
Jambrina P, Rauch N, Pilkington R, Rybakova K, Nguyen L, Kholodenko B, Buchete N, Kolch W, Rosta E. Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation. Angewandte Chemie 2015, 128: 995-998. DOI: 10.1002/ange.201509272.Peer-Reviewed Original ResearchRAF dimerizationStructure-based mechanismPhysiological activation mechanismKinase dimerΑC-helixAcidic motifRaf kinaseRAF dimersR-spineConformational changesTrp residuesRAF inhibitorsPhosphorylationActivation mechanismKey playersSalt bridgeMotifKinaseCooperative interactionsRafPersonalized cancer therapyActive siteImportant targetResiduesPathway
2013
Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers
Hu J, Stites E, Yu H, Germino E, Meharena H, Stork P, Kornev A, Taylor S, Shaw A. Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers. Cell 2013, 154: 1036-1046. PMID: 23993095, PMCID: PMC3844432, DOI: 10.1016/j.cell.2013.07.046.Peer-Reviewed Original ResearchMeSH KeywordsAllosteric RegulationAmino Acid MotifsAmino Acid SequenceAnimalsCell LineDimerizationEnzyme ActivationHumansMiceModels, MolecularMolecular Sequence DataMutationPhosphorylationProtein ConformationProtein KinasesProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-rafraf KinasesSequence AlignmentTryptophanConceptsN-terminal phosphorylationReceiver kinaseRaf kinaseActivation-loop phosphorylationPhosphorylation of CRAFConstitutively active mutantCis-autophosphorylationRaf activationActive mutantActivated CRAFActive kinaseMechanism of activationKinase activityActive conformationKinasePhosphorylationControl cellsRafCRAFDimerMutantsRasActivityMEKBRAF
2009
C-Raf Is Associated with Disease Progression and Cell Proliferation in a Subset of Melanomas
Jilaveanu LB, Zito CR, Aziz SA, Conrad PJ, Schmitz JC, Sznol M, Camp RL, Rimm DL, Kluger HM. C-Raf Is Associated with Disease Progression and Cell Proliferation in a Subset of Melanomas. Clinical Cancer Research 2009, 15: 5704-5713. PMID: 19737955, PMCID: PMC2763114, DOI: 10.1158/1078-0432.ccr-09-0198.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overBenzenesulfonatesCell Line, TumorCell ProliferationCell SurvivalCohort StudiesDisease ProgressionFemaleGene SilencingHumansIndolesMaleMelanomaMiddle AgedNevusNiacinamidePhenolsPhenylurea CompoundsProtein Kinase InhibitorsProto-Oncogene Proteins c-rafPyridinesRNA, Small InterferingSensitivity and SpecificitySkin NeoplasmsSorafenibYoung AdultConceptsExtracellular signal-regulated kinaseC-RafC-Raf expressionSubset of melanomasPhospho-c-RafSignal-regulated kinaseCell linesProtein kinase inhibitionMitogen-activated protein kinase inhibitionDecreased viabilityDecreased Bcl-2 expressionProtein kinaseCell signalingBcl-2 inhibitionRaf kinaseB-RafMelanoma cell linesPhospho-MEKSpecific siRNAsSitu protein expressionGW5074Major isoformsKinasePhospho-ERKBcl-2 expression
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