2024
Structural insights into the role and targeting of EGFRvIII
Bagchi A, Stayrook S, Xenaki K, Starbird C, Doulkeridou S, El Khoulati R, Roovers R, Schmitz K, van Bergen En Henegouwen P, Ferguson K. Structural insights into the role and targeting of EGFRvIII. Structure 2024, 32: 1367-1380.e6. PMID: 38908376, PMCID: PMC11380598, DOI: 10.1016/j.str.2024.05.018.Peer-Reviewed Original Research
2022
Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias
Hu C, Leche CA, Kiyatkin A, Yu Z, Stayrook SE, Ferguson KM, Lemmon MA. Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias. Nature 2022, 602: 518-522. PMID: 35140400, PMCID: PMC8857055, DOI: 10.1038/s41586-021-04393-3.Peer-Reviewed Original Research
2020
Insulin and epidermal growth factor receptor family members share parallel activation mechanisms
Ferguson KM, Hu C, Lemmon MA. Insulin and epidermal growth factor receptor family members share parallel activation mechanisms. Protein Science 2020, 29: 1331-1344. PMID: 32297376, PMCID: PMC7255510, DOI: 10.1002/pro.3871.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsReceptor tyrosine kinasesEpidermal growth factor receptorLigand-binding moduleInsulin receptorAutoinhibitory interactionsRecent cryo-electron microscopy structuresCryo-electron microscopy structureFirst receptor tyrosine kinasesRecent cryo-EM structureEGFR activation mechanismsEpidermal growth factor receptor family membersActivated insulin receptorIntramolecular autoinhibitory interactionCryo-EM structureActivation mechanismCysteine-rich domainFibronectin type III domainReceptor family membersEGFR family membersType III domainMicroscopy structureDomain compositionTransmembrane regionGrowth factor receptorLike domain
2018
Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain
Emptage RP, Lemmon MA, Ferguson KM, Marmorstein R. Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain. Structure 2018, 26: 1137-1143.e3. PMID: 30099988, PMCID: PMC6092042, DOI: 10.1016/j.str.2018.05.008.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesCheckpoint Kinase 1Cloning, MolecularCrystallography, X-RayEscherichia coliGene ExpressionGenetic VectorsHumansKineticsModels, MolecularMutationPeptidesProtein BindingProtein Conformation, alpha-HelicalProtein Conformation, beta-StrandProtein Interaction Domains and MotifsProtein Serine-Threonine KinasesRecombinant ProteinsStructural Homology, ProteinSubstrate SpecificityThermodynamicsConceptsKA1 domainSer/Thr protein kinaseKinase structureRelated kinasesUBA domainKinase domainProtein kinaseStructural basisC-terminusUnexpected interfaceC-lobeKinaseΑD helixPotential new avenuesAutoinhibitoryData implicateDomain surfaceDomainNew avenuesYeastAutoinhibitionCrystal structureHelixAlzheimer's diseaseVariantsMolecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance.
Bagchi A, Haidar JN, Eastman SW, Vieth M, Topper M, Iacolina MD, Walker JM, Forest A, Shen Y, Novosiadly RD, Ferguson KM. Molecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance. Molecular Cancer Therapeutics 2018, 17: molcanther.0575.2017. PMID: 29158469, PMCID: PMC5925748, DOI: 10.1158/1535-7163.mct-17-0575.Peer-Reviewed Original Research
2017
EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics
Freed DM, Bessman NJ, Kiyatkin A, Salazar-Cavazos E, Byrne PO, Moore JO, Valley CC, Ferguson KM, Leahy DJ, Lidke DS, Lemmon MA. EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics. Cell 2017, 171: 683-695.e18. PMID: 28988771, PMCID: PMC5650921, DOI: 10.1016/j.cell.2017.09.017.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesEpidermal growth factor receptorEGFR ligandsEGFR extracellular regionG protein-coupled receptorsDifferent EGFR ligandsCellular programsDifferent activating ligandsEGFR dimersCell signalingGrowth factor receptorExtracellular regionDimeric conformationEGFR dimerizationNew therapeutic opportunitiesReceptor dimersTyrosine kinaseBreast cancer cellsDimerization strengthActivating ligandsFactor receptorCancer cellsEpigenTherapeutic opportunitiesBiased agonismIntramolecular autoinhibition of checkpoint kinase 1 is mediated by conserved basic motifs of the C-terminal kinase–associated 1 domain
Emptage RP, Schoenberger MJ, Ferguson KM, Marmorstein R. Intramolecular autoinhibition of checkpoint kinase 1 is mediated by conserved basic motifs of the C-terminal kinase–associated 1 domain. Journal Of Biological Chemistry 2017, 292: 19024-19033. PMID: 28972186, PMCID: PMC5704483, DOI: 10.1074/jbc.m117.811265.Peer-Reviewed Original ResearchConceptsKA1 domainIntramolecular autoinhibitionSer/Thr proteinKinase 1N-terminal kinase domainChk1 kinase activityKey regulatory mechanismTerminal regulatory regionDNA damage repairSite-directed mutagenesisCheckpoint kinase 1Thr proteinChk1 kinaseHuman Chk1Truncation mutantsKinase domainRegulatory regionsKinase activityBasic residuesDamage repairRegulatory mechanismsStructural homologyResidue linkerCell cyclePrimary structureDimerization of Tie2 mediated by its membrane-proximal FNIII domains
Moore JO, Lemmon MA, Ferguson KM. Dimerization of Tie2 mediated by its membrane-proximal FNIII domains. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 4382-4387. PMID: 28396397, PMCID: PMC5410832, DOI: 10.1073/pnas.1617800114.Peer-Reviewed Original ResearchConceptsExtracellular regionFNIII domainsResolution X-ray crystal structureMembrane-proximal fibronectin type III domainsDomain-mediated interactionsDifferent cellular contextsLigand-binding regionHigher-order oligomersTie2 activationFibronectin type III domainReceptor tyrosine kinasesTyrosine kinase familyEGF-homology domainThird FNIII domainType III domainPrevious structural studiesStructural studiesHomology domainCellular contextKinase familyDimer interfaceDimerization modeReceptor dimerizationTyrosine kinasePrimary activatorMolecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase.
Emptage RP, Lemmon MA, Ferguson KM. Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase. Biochemical Journal 2017, 474: 385-398. PMID: 27879374, PMCID: PMC5317272, DOI: 10.1042/bcj20160792.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsBinding SitesCloning, MolecularEnzyme AssaysEscherichia coliGene ExpressionHumansKineticsMitogen-Activated Protein Kinase 1Models, MolecularPeptidesPhospholipidsProtein BindingProtein Interaction Domains and MotifsProtein Structure, SecondaryRecombinant ProteinsScattering, Small AngleSubstrate SpecificityX-Ray DiffractionConceptsKA1 domainMAP/microtubule affinity-regulating kinasesMicrotubule affinity-regulating kinaseGroup of kinasesIntramolecular autoinhibitory interactionAnionic phospholipid bindingAnionic phospholipidsSite-directed mutagenesisAutoinhibitory interactionsRegulatory modulesAutoinhibitory roleProtein modulesMembrane-bound targetsRelated kinasesBind membranesFamily kinasesKinase domainProtein kinasePhospholipid activationC-terminusRegulatory mechanismsPhospholipid bindingMechanistic basisKinaseAutoinhibitory activity