2025
Allosteric inhibition of the IZUMO1–JUNO fertilization complex by the naturally occurring antisperm antibody OBF13
Lu Y, Ikawa M, Tang S. Allosteric inhibition of the IZUMO1–JUNO fertilization complex by the naturally occurring antisperm antibody OBF13. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2425952122. PMID: 40042902, PMCID: PMC11912406, DOI: 10.1073/pnas.2425952122.Peer-Reviewed Original ResearchConceptsFour-helix domainAllosteric inhibitionBinding of acrosome-reacted spermAcrosome-reacted spermSperm-egg interactionDeep mutational scanningX-ray crystal structureMurine spermSingle-chain fragment variablesSperm IZUMO1IZUMO1Mutational scanningMammalian fertilizationApparent affinityHamster eggsMurine fertilizationSpecies-specificSpermMurine eggsAntisperm antibodiesFragment variablesConformational changesSomatic hypermutationAntispermLow levels of somatic hypermutation
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
Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors
Gannam Z, Jamali H, Kweon OS, Herrington J, Shillingford SR, Papini C, Gentzel E, Lolis E, Bennett AM, Ellman JA, Anderson KS. Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors. European Journal Of Medicinal Chemistry 2022, 243: 114712. PMID: 36116232, PMCID: PMC9830533, DOI: 10.1016/j.ejmech.2022.114712.Peer-Reviewed Original ResearchMeSH KeywordsStructure-Activity RelationshipConceptsStress-responsive MAPKsEnzyme-inhibitor complexDystrophic muscle diseasePhosphatase 5Muscle diseaseAllosteric inhibitorsNumber of diseasesNovel classProtein kinase phosphatase 5Structure-activity relationshipsPotential therapeutic targetMKP5X-ray crystal structureTherapeutic targetPotential therapeuticsInhibitorsLead compoundsInhibitionProper positioningMAPKCrystal structureMitogenTyr435Derivative compoundsInteractionDe novo protein design of photochemical reaction centers
Ennist N, Zhao Z, Stayrook S, Discher B, Dutton P, Moser C. De novo protein design of photochemical reaction centers. Nature Communications 2022, 13: 4937. PMID: 35999239, PMCID: PMC9399245, DOI: 10.1038/s41467-022-32710-5.Peer-Reviewed Original ResearchConceptsCharge separationSolar-to-fuel energy conversionReaction centerLight-driven charge separationX-ray crystal structurePhotosynthetic reaction center proteinCharge separation lifetimeSolar fuel productionTransient absorption spectroscopyPhotosynthetic reaction centersPhotochemical charge separationModify natural proteinsPhotochemical reaction centerReaction center proteinCluster oxidationRedox centersCrystal structureAbsorption spectroscopyElectron transfer activityNatural protein structuresDe novo protein designPhotosynthetic protein complexesEnergy conversionX-rayProtein frameworkGlycerol binding at the narrow channel of photosystem II stabilizes the low-spin S2 state of the oxygen-evolving complex
Flesher DA, Liu J, Wiwczar JM, Reiss K, Yang KR, Wang J, Askerka M, Gisriel CJ, Batista VS, Brudvig GW. Glycerol binding at the narrow channel of photosystem II stabilizes the low-spin S2 state of the oxygen-evolving complex. Photosynthesis Research 2022, 152: 167-175. PMID: 35322325, PMCID: PMC9427693, DOI: 10.1007/s11120-022-00911-0.Peer-Reviewed Original ResearchConceptsOxygen-evolving complexHydrogen bond networkS2 stateEPR signalPhotosystem II cyclesX-ray crystal structureRelative stabilityState EPR signalsD1-Asp61Water oxidationCatalytic intermediatesPhotochemical oxidationEPR spectraGlycerol moleculesCrystal structureCyanobacterial PSIIMultiline signalState SiPhotosystem IIOxidationRelative intensitiesComplexesEffect of glycerolExperimental conditionsStability
2021
Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV‑2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations
Zhang CH, Stone EA, Deshmukh M, Ippolito JA, Ghahremanpour MM, Tirado-Rives J, Spasov KA, Zhang S, Takeo Y, Kudalkar SN, Liang Z, Isaacs F, Lindenbach B, Miller SJ, Anderson KS, Jorgensen WL. Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV‑2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations. ACS Central Science 2021, 7: 467-475. PMID: 33786375, PMCID: PMC7931627, DOI: 10.1021/acscentsci.1c00039.Peer-Reviewed Original ResearchFree energy perturbation calculationsX-ray crystal structurePotent noncovalent inhibitorMain proteaseHigh-resolution X-ray crystal structuresCell-based antiviral assaysComputational chemistryLigand complexesNoncovalent inhibitorsCrystal structureNonpeptidic inhibitorsLead optimizationDrug discoveryPerturbation calculationsNM ICPotent analoguesKinetic assaysPossible therapeutic significanceNoncovalentChemistryAnaloguesValuable guidanceCalculationsCompoundsComplexes
2020
The GTPase-activating protein p120RasGAP has an evolutionarily conserved “FLVR-unique” SH2 domain
Jaber Chehayeb R, Wang J, Stiegler AL, Boggon TJ. The GTPase-activating protein p120RasGAP has an evolutionarily conserved “FLVR-unique” SH2 domain. Journal Of Biological Chemistry 2020, 295: 10511-10521. PMID: 32540970, PMCID: PMC7397115, DOI: 10.1074/jbc.ra120.013976.Peer-Reviewed Original ResearchConceptsC-terminal SH2 domainSH2 domainFLVR motifSrc homology 2 domainArginine residuesSalt bridgePhosphotyrosine motifsPeptide-bound formsPhosphopeptide bindingUnrecognized diversityDirect salt bridgeIntramolecular salt bridgeIsothermal titration calorimetryPhosphotyrosineP120RasGAPMotifX-ray crystal structureTitration calorimetryAspartic acidTandem substitutionsResiduesBindingDomainGTPaseP190RhoGAP
2019
Crystal structures of p120RasGAP N-terminal SH2 domain in its apo form and in complex with a p190RhoGAP phosphotyrosine peptide
Chehayeb R, Stiegler AL, Boggon TJ. Crystal structures of p120RasGAP N-terminal SH2 domain in its apo form and in complex with a p190RhoGAP phosphotyrosine peptide. PLOS ONE 2019, 14: e0226113. PMID: 31891593, PMCID: PMC6938330, DOI: 10.1371/journal.pone.0226113.Peer-Reviewed Original ResearchConceptsN-terminal SH2 domainSH2 domainPhosphotyrosine peptidesNative gel shiftSite-directed mutagenesisGAP proteinsCo-crystal structurePhosphorylated tyrosineRas pathwayUnliganded formApo formCross-talk occursGel shiftP120RasGAPIsothermal titration calorimetryP190RhoGAPCell growthSpecific conformationCell proliferationProteinX-ray crystal structureTitration calorimetryDisease pathogenesisCrystal structureRhoA high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery
Tang S, Kim P. A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 24500-24506. PMID: 31727844, PMCID: PMC6900541, DOI: 10.1073/pnas.1916916116.Peer-Reviewed Original ResearchConceptsX-ray crystal structureImmune checkpoint blockadePD-1 inhibitorsPD-1PD-L2Human PD-1Ligand-bound conformationSmall-molecule drug targetsCrystal structureBlockade of programmed death-1PD-1 variantFG loopX-rayWild-type proteinYeast surface displayDeep mutational scanningDrug discoveryLigand-binding surfaceCC' loopMurine PD-1Monoclonal antibody drugsConformational changesDeath-1Treatment of cancerMutational scanningVisualization of H atoms in the X‐ray crystal structure of photoactive yellow protein: Does it contain low‐barrier hydrogen bonds?
Wang J. Visualization of H atoms in the X‐ray crystal structure of photoactive yellow protein: Does it contain low‐barrier hydrogen bonds? Protein Science 2019, 28: 1966-1972. PMID: 31441173, PMCID: PMC6798185, DOI: 10.1002/pro.3716.Peer-Reviewed Original ResearchConceptsPhotoactive yellow proteinLow-barrier hydrogen bondH atomsYellow proteinResidual electron density mapsNeutron structureAtomsO bond angleO distancesO atomsHydrogen bondsElectron density mapsBond anglesDensity mapsX-ray structureCrystal structureResolution X-ray structureStructureBondsX-ray crystal structure
2018
Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor
Nelson CA, Wilen CB, Dai YN, Orchard RC, Kim AS, Stegeman RA, Hsieh LL, Smith TJ, Virgin HW, Fremont DH. Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e9201-e9210. PMID: 30194229, PMCID: PMC6166816, DOI: 10.1073/pnas.1805797115.Peer-Reviewed Original ResearchConceptsP domainCognate cellular receptorDomain dimer interfaceDimer interfaceBiophysical assaysStructural basisCD300lfResidue mutationsP2 subdomainAcid bindingCell surfaceHost ligandsCellular receptorsProtruding (P) domainStructural determinantsDE loopMonomeric affinityBinding sitesX-ray crystal structurePotential modulatorsReceptor binding sitesMNoVCrystal structureDivalent cationsReceptors
2017
X‑ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors
Witten MR, Wissler L, Snow M, Geschwindner S, Read JA, Brandon NJ, Nairn AC, Lombroso PJ, Käck H, Ellman JA. X‑ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors. Journal Of Medicinal Chemistry 2017, 60: 9299-9319. PMID: 29116812, PMCID: PMC5758861, DOI: 10.1021/acs.jmedchem.7b01292.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseProtein tyrosine phosphatase inhibitorProtein tyrosine phosphataseTyrosine phosphatase inhibitorFirst X-ray crystal structureTyrosine phosphatasePhosphatase inhibitorSTEP inhibitorPhosphorylation levelsInhibitor structureSubstrate-based approachNumerous neuropsychiatric disordersX-ray crystal structureDrug discoverySTEP substratesStructural informationPhosphataseInhibitorsMouse modelKnockdownSurprising findingCrystal structureNeuropsychiatric disordersExcessive activityAlzheimer's diseaseJAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules
Newton AS, Deiana L, Puleo DE, Cisneros J, Cutrona KJ, Schlessinger J, Jorgensen WL. JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules. ACS Medicinal Chemistry Letters 2017, 8: 614-617. PMID: 28626520, PMCID: PMC5467202, DOI: 10.1021/acsmedchemlett.7b00154.Peer-Reviewed Original Research
2016
Diversity of Secondary Structure in Catalytic Peptides with β‑Turn-Biased Sequences
Metrano AJ, Abascal NC, Mercado BQ, Paulson EK, Hurtley AE, Miller SJ. Diversity of Secondary Structure in Catalytic Peptides with β‑Turn-Biased Sequences. Journal Of The American Chemical Society 2016, 139: 492-516. PMID: 28029251, PMCID: PMC5312972, DOI: 10.1021/jacs.6b11348.Peer-Reviewed Original ResearchConceptsPeptide-based catalystsSolid-state structural featuresΒ-turn secondary structureX-ray crystal structureProton chemical shiftsCorresponding solution structuresSymmetry-independent moleculesX-ray crystallographyAccessible transition stateGround state conformationSeries of tetrapeptidesChemical shiftsDifferent peptide sequencesEnantioselective reactionsSecondary structureCatalytic activityBromination reactionSame unit cellCatalytic peptidesTransition stateCrystal structureCatalystState conformationComputational studyConformational equilibrium376 The x-ray crystal structure of a keratin 1–keratin 10 heterocomplex demonstrates how patient mutations disrupt protein chemistry to cause human keratinopathies
Bunick C. 376 The x-ray crystal structure of a keratin 1–keratin 10 heterocomplex demonstrates how patient mutations disrupt protein chemistry to cause human keratinopathies. Journal Of Investigative Dermatology 2016, 136: s67. DOI: 10.1016/j.jid.2016.02.409.Peer-Reviewed Original ResearchESCRT-III activation by parallel action of ESCRT-I/II and ESCRT-0/Bro1 during MVB biogenesis
Tang S, Buchkovich N, Henne W, Banjade S, Kim Y, Emr S. ESCRT-III activation by parallel action of ESCRT-I/II and ESCRT-0/Bro1 during MVB biogenesis. ELife 2016, 5: e15507. PMID: 27074665, PMCID: PMC4865371, DOI: 10.7554/elife.15507.Peer-Reviewed Original ResearchMeSH KeywordsCell MembraneEndosomal Sorting Complexes Required for TransportGene Expression Regulation, FungalMultivesicular BodiesMutationProtein DomainsProtein Structure, SecondaryProtein TransportSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSignal TransductionUbiquitinated ProteinsUbiquitinationConceptsESCRT-III activityESCRT-IIIESCRT-III-mediated membrane remodelingESCRT-III subunit Snf7N-terminal core domainESCRT-III subunitsMembrane remodeling eventsEndosomal Sorting ComplexUbiquitin-dependent pathwayUpstream ESCRTsFunctional divergenceMVB biogenesisESCRT componentsSorting complexMembrane remodelingC-terminusSnf7Molecular explanationRemodeling eventsCore domainOrthologsPolymerization stateYeastX-ray crystal structurePathway
2015
Synthetic Metallochaperone ZMC1 Rescues Mutant p53 Conformation by Transporting Zinc into Cells as an Ionophore
Blanden AR, Yu X, Wolfe AJ, Gilleran JA, Augeri DJ, O'Dell RS, Olson EC, Kimball SD, Emge TJ, Movileanu L, Carpizo DR, Loh SN. Synthetic Metallochaperone ZMC1 Rescues Mutant p53 Conformation by Transporting Zinc into Cells as an Ionophore. Molecular Pharmacology 2015, 87: 825-831. PMID: 25710967, PMCID: PMC4407733, DOI: 10.1124/mol.114.097550.Peer-Reviewed Original ResearchConceptsHuman embryonic kidney cell line 293Mutant p53 conformationEssential zinc ionCell line 293Mutant proteinsP53-R175HPlasma membraneExtracellular environmentP53 conformationTumor suppressorLiving cellsHuman cancersBinding sitesX-ray crystal structureCommon mutationsObserved reactivationCellsZinc ionsMetallochaperoneVivo activityMutantsSuppressorOrganismsProteinR175HComparison of Saccharomyces cerevisiae F-BAR Domain Structures Reveals a Conserved Inositol Phosphate Binding Site
Moravcevic K, Alvarado D, Schmitz KR, Kenniston JA, Mendrola JM, Ferguson KM, Lemmon MA. Comparison of Saccharomyces cerevisiae F-BAR Domain Structures Reveals a Conserved Inositol Phosphate Binding Site. Structure 2015, 23: 352-363. PMID: 25620000, PMCID: PMC4319572, DOI: 10.1016/j.str.2014.12.009.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBinding SitesCrystallography, X-RayGreen Fluorescent ProteinsGTPase-Activating ProteinsHeLa CellsHumansInositol PhosphatesModels, MolecularMolecular Sequence DataProtein Structure, TertiarySaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSequence AlignmentSpecies SpecificityConceptsF-BAR domainLipid-binding specificityMembrane-binding propertiesNumerous functional studiesPhosphate binding siteUnappreciated determinantF-BARDomain bindsCell signalingCurved membranesMembrane interactionsFunctional studiesRgd1pBinding sitesX-ray crystal structureInositol phosphatesDomain structureDomainHof1pPhospholipidsRhoGAPCytokinesisEndocytosisPhosphoinositideSignalingComputational Insights on Crystal Structures of the Oxygen-Evolving Complex of Photosystem II with Either Ca2+ or Ca2+ Substituted by Sr2+
Vogt L, Ertem MZ, Pal R, Brudvig GW, Batista VS. Computational Insights on Crystal Structures of the Oxygen-Evolving Complex of Photosystem II with Either Ca2+ or Ca2+ Substituted by Sr2+. Biochemistry 2015, 54: 820-825. PMID: 25555204, DOI: 10.1021/bi5011706.Peer-Reviewed Original ResearchConceptsX-ray crystal structureCrystal structureQuantum mechanics/molecular mechanics calculationsQM/MM modelOxygen-evolving complexMolecular mechanics calculationsPhotosystem IIWater oxidationMechanics calculationsComputational insightsReduced statesHeterocationsMM modelSubstitution resultsComplexesS statesStructureCationsBondsOxidationSr2Experimental dataW5WaterCalculationsStructural basis for activation, assembly and membrane binding of ESCRT-III Snf7 filaments
Tang S, Henne W, Borbat P, Buchkovich N, Freed J, Mao Y, Fromme J, Emr S. Structural basis for activation, assembly and membrane binding of ESCRT-III Snf7 filaments. ELife 2015, 4: e12548. PMID: 26670543, PMCID: PMC4720517, DOI: 10.7554/elife.12548.Peer-Reviewed Original ResearchConceptsPulsed dipolar electron spin resonance spectroscopyESCRT-III subunitsESCRT-IIIESCRT-III-mediated membrane remodelingESCRT-III subunit Snf7Membrane-remodeling processesEndosomal Sorting ComplexProtein-protein interfacesX-ray crystal structureESCRT functionSorting complexMembrane remodelingGenetic approachesMembrane bindingProtein interfacesElectron spin resonance spectroscopyActive conformationStructural basisSnf7Conformational rearrangementsProtein-membraneSpin resonance spectroscopyCrystal structureX-raySubunit
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