2025
Structural basis for aminoacylation of cellular modified tRNALys3 by human lysyl-tRNA synthetase
Devarkar S, Budding C, Pathirage C, Kavoor A, Herbert C, Limbach P, Musier-Forsyth K, Xiong Y. Structural basis for aminoacylation of cellular modified tRNALys3 by human lysyl-tRNA synthetase. Nucleic Acids Research 2025, 53: gkaf114. PMID: 40036503, PMCID: PMC11878792, DOI: 10.1093/nar/gkaf114.Peer-Reviewed Original ResearchConceptsTransfer ribonucleic acidHuman lysyl-tRNA synthetaseLysyl-tRNA synthetaseHigh-resolution cryo-electron microscopyPost-transcriptional modificationsCryo-electron microscopyD-loopCatalytic stepStructural basisAminoacylationCryo-EMProtein synthesisCatalytic efficiencyFunctional impactSynthetaseRibonucleic acidActive siteMachineryLysRSMetazoansMs2t6ATRNALys3Mcm5s2UR37Integral role
2024
Photosystem II: light-dependent oscillation of ligand composition at its active site
Wang J. Photosystem II: light-dependent oscillation of ligand composition at its active site. Acta Crystallographica Section D, Structural Biology 2024, 80: 850-861. PMID: 39607822, DOI: 10.1107/s2059798324011392.Peer-Reviewed Original ResearchMeSH KeywordsCatalytic DomainCrystallography, X-RayLigandsLightModels, MolecularOxygenPhotosystem II Protein ComplexThermosynechococcusA salt bridge of the C‐terminal carboxyl group regulates PHPT1 substrate affinity and catalytic activity
Zavala E, Dansereau S, Burke M, Lipchock J, Maschietto F, Batista V, Loria J. A salt bridge of the C‐terminal carboxyl group regulates PHPT1 substrate affinity and catalytic activity. Protein Science 2024, 33: e5009. PMID: 38747379, PMCID: PMC11094782, DOI: 10.1002/pro.5009.Peer-Reviewed Original ResearchConceptsCatalytic activityPhenylphosphonic acidAnalysis of molecular dynamics trajectoriesNMR chemical shiftsSalt bridgesMolecular dynamics trajectoriesC-terminal carboxyl groupChemical shiftsCombination of solution NMRMolecular dynamicsGuanidinium moietyCarboxyl groupsPara-nitrophenylphosphateSolution NMRActive site inhibitorsHistidine phosphataseActive siteElectrostatic interactionsDynamics trajectoriesEnzymatic functionC-terminusGlycine residuesSubstrate affinityBiochemical experimentsBinding affinityPositive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB
Lampson B, Ramίrez A, Baro M, He L, Hegde M, Koduri V, Pfaff J, Hanna R, Kowal J, Shirole N, He Y, Doench J, Contessa J, Locher K, Kaelin W. Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB. Cell 2024, 187: 2209-2223.e16. PMID: 38670073, PMCID: PMC11149550, DOI: 10.1016/j.cell.2024.03.022.Peer-Reviewed Original ResearchConceptsWhole-genome CRISPR-Cas9 screenCRISPR-Cas9 screensCryoelectron microscopy studiesCell surface localizationLipopolysaccharide receptor Toll-like receptor 4OST complexToll-like receptor 4CRISPR screensNF-kBCatalytic subunitN-glycosylationActivate NF-kBBase editorsUncompetitive inhibition mechanismNGI-1Molecular mechanismsCatalytic siteLPS-treated cellsOligosaccharyltransferaseDruggable pocketSTT3AReceptor Toll-like receptor 4Drug mechanism of actionStructural studiesInflammatory signaling
2023
KDM5 Lysine Demethylases in Pathogenesis, from Basic Science Discovery to the Clinic
Zhang S, Cao J, Yan Q. KDM5 Lysine Demethylases in Pathogenesis, from Basic Science Discovery to the Clinic. Advances In Experimental Medicine And Biology 2023, 1433: 113-137. PMID: 37751138, DOI: 10.1007/978-3-031-38176-8_6.ChaptersConceptsPlant homeodomainFamily proteinsKey epigenetic markCell fate determinationHistone methylation marksCancer type-dependent mannerKetoglutarate-dependent dioxygenasesSelective KDM5 inhibitorsTumor suppressive functionType-dependent mannerEpigenetic marksTumor suppressive roleFate determinationJumonji CLysine 4Active chromatinMethylation marksHistone H3Lysine demethylasesCatalytic coreKDM5 inhibitorsDrug targetsKDM5Cancer metastasisSuppressive role
2022
Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells
Lynall ME, Soskic B, Hayhurst J, Schwartzentruber J, Levey DF, Pathak GA, Polimanti R, Gelernter J, Stein MB, Trynka G, Clatworthy MR, Bullmore E. Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells. Nature Communications 2022, 13: 6102. PMID: 36243721, PMCID: PMC9569335, DOI: 10.1038/s41467-022-33885-7.Peer-Reviewed Original ResearchConceptsMultiple psychiatric disordersPsychiatric disordersPsychiatric risk variantT cellsLymphoid cellsRisk variantsImmune cell subsetsMental health disordersMultiple organ systemsAdaptive immune systemCell subsetsImmune cellsHealth disordersMyeloid cellsImmune systemBrain tissueOrgan systemsSpecific disordersDisordersPathogenesisAbnormalitiesGenetic variantsCellsCD4VariantsRare pathogenic variants in WNK3 cause X-linked intellectual disability
Küry S, Zhang J, Besnard T, Caro-Llopis A, Zeng X, Robert SM, Josiah SS, Kiziltug E, Denommé-Pichon AS, Cogné B, Kundishora AJ, Hao LT, Li H, Stevenson RE, Louie RJ, Deb W, Torti E, Vignard V, McWalter K, Raymond FL, Rajabi F, Ranza E, Grozeva D, Coury SA, Blanc X, Brischoux-Boucher E, Keren B, Õunap K, Reinson K, Ilves P, Wentzensen IM, Barr EE, Guihard SH, Charles P, Seaby EG, Monaghan KG, Rio M, van Bever Y, van Slegtenhorst M, Chung WK, Wilson A, Quinquis D, Bréhéret F, Retterer K, Lindenbaum P, Scalais E, Rhodes L, Stouffs K, Pereira EM, Berger SM, Milla SS, Jaykumar AB, Cobb MH, Panchagnula S, Duy PQ, Vincent M, Mercier S, Gilbert-Dussardier B, Le Guillou X, Audebert-Bellanger S, Odent S, Schmitt S, Boisseau P, Bonneau D, Toutain A, Colin E, Pasquier L, Redon R, Bouman A, Rosenfeld JA, Friez MJ, Pérez-Peña H, Akhtar Rizvi SR, Haider S, Antonarakis SE, Schwartz CE, Martínez F, Bézieau S, Kahle KT, Isidor B. Rare pathogenic variants in WNK3 cause X-linked intellectual disability. Genetics In Medicine 2022, 24: 1941-1951. PMID: 35678782, DOI: 10.1016/j.gim.2022.05.009.Peer-Reviewed Original ResearchConceptsPathogenic missense variantsMissense variantsIntellectual disabilityCation-chloride cotransportersGenome sequenceCatalytic domainInhibitory phosphorylationStructural brain abnormalitiesStructural brain defectsRare pathogenic variantsLarge familyWNK3Synaptic inhibitionCotransporter KCC2Brain abnormalitiesRare formPathogenic mechanismsDifferent familiesSporadic formsPathogenic variantsBrain defectsUnrelated familiesAffected individualsKCC2EpilepsyTousled-like kinase 2 targets ASF1 histone chaperones through client mimicry
Simon B, Lou HJ, Huet-Calderwood C, Shi G, Boggon TJ, Turk BE, Calderwood DA. Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry. Nature Communications 2022, 13: 749. PMID: 35136069, PMCID: PMC8826447, DOI: 10.1038/s41467-022-28427-0.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceCatalytic DomainCell Cycle ProteinsConserved SequenceCrystallography, X-RayHistonesHumansMolecular ChaperonesMolecular Docking SimulationMolecular MimicryMutagenesisPeptide LibraryPhosphorylationProtein KinasesRecombinant ProteinsSubstrate SpecificityConceptsTousled-like kinaseDNA replication-coupled nucleosome assemblyNuclear serine-threonine kinaseReplication-coupled nucleosome assemblyHistone chaperone proteinsGlobular N-terminal domainProper cell divisionPhosphorylation site motifsSerine-threonine kinaseShort sequence motifsAsf1 histone chaperonesC-terminal tailN-terminal domainHistone chaperonesGenome maintenanceNucleosome assemblySequence motifsChaperone proteinsNon-catalytic interactionsCatalytic domainCell divisionSite motifN-terminusStringent selectivityCell growth
2021
Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs)
Chen PH, Hu Z, An E, Okeke I, Zheng S, Luo X, Gong A, Jaime-Figueroa S, Crews CM. Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs). ACS Chemical Biology 2021, 16: 2808-2815. PMID: 34780684, PMCID: PMC10437008, DOI: 10.1021/acschembio.1c00693.Peer-Reviewed Original ResearchConceptsSer/Thr phosphataseChemical biology approachPP2A holoenzymeProtein dephosphorylationBiology approachProtein substratesTranscriptional activationProtein phosphorylationCatalytic subunitCell biologyReporter geneProtein activityRetinoblastoma proteinOff-target effectsCritical proteinsDephosphorylationTernary complexPhosphorylationKinase inhibitorsFOXO3aPROTACsProteinChimerasPhosphataseDrug resistanceA structurally preserved allosteric site in the MIF superfamily affects enzymatic activity and CD74 activation in D-dopachrome tautomerase
Chen E, Reiss K, Shah D, Manjula R, Allen B, Murphy EL, Murphy JW, Batista VS, Bhandari V, Lolis EJ, Lisi GP. A structurally preserved allosteric site in the MIF superfamily affects enzymatic activity and CD74 activation in D-dopachrome tautomerase. Journal Of Biological Chemistry 2021, 297: 101061. PMID: 34384784, PMCID: PMC8405996, DOI: 10.1016/j.jbc.2021.101061.Peer-Reviewed Original ResearchMeSH KeywordsAllosteric SiteAmino Acid SequenceAntigens, Differentiation, B-LymphocyteBinding SitesCatalytic DomainCrystallography, X-RayCytokinesHistocompatibility Antigens Class IIHumansIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsProtein BindingStructure-Activity RelationshipConceptsAllosteric siteDopachrome tautomeraseDynamic regulatory networksEnzymatic activityLow sequence identityLigand-binding siteMultiple ligand-binding sitesNonoverlapping functionsRegulatory networksAllosteric couplingMacrophage migration inhibitory factor (MIF) familyFactor familySequence identityHomolog DStructural basisPrimary sequenceCD74 activationFunctional similarityConformational changesSolution NMRMIF-2X-ray crystallographyCatalytic siteStructural consequencesSolvent channelsStructure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease
Deshmukh MG, Ippolito JA, Zhang CH, Stone EA, Reilly RA, Miller SJ, Jorgensen WL, Anderson KS. Structure-guided design of a perampanel-derived pharmacophore targeting the SARS-CoV-2 main protease. Structure 2021, 29: 823-833.e5. PMID: 34161756, PMCID: PMC8218531, DOI: 10.1016/j.str.2021.06.002.Peer-Reviewed Original ResearchConceptsMain proteaseSARS-CoV-2 main proteaseActive site flexibilityDetailed structural insightsStructure-activity relationshipsInhibitor design effortsLow micromolar rangeActive site cysteineChemical scaffoldsLow nanomolar rangeCovalent adductsStructure-guided designCrystal structureStructural insightsPharmacophoreAdductsAttractive targetScaffoldsCysteineAnaloguesMechanism of actionSupRangeStructureThe nucleotide binding affinities of two critical conformations of Escherichia coli ATP synthase
Li Y, Valdez NA, Mnatsakanyan N, Weber J. The nucleotide binding affinities of two critical conformations of Escherichia coli ATP synthase. Archives Of Biochemistry And Biophysics 2021, 707: 108899. PMID: 33991499, PMCID: PMC8278868, DOI: 10.1016/j.abb.2021.108899.Peer-Reviewed Original ResearchMeSH KeywordsCatalytic DomainEscherichia coliModels, MolecularNucleotidesProtein BindingProton-Translocating ATPasesConceptsATP synthaseCritical conformationEscherichia coli ATP synthaseRotary catalytic mechanismCatalytic dwell stateCatalytic mechanismAerobic energy metabolismΓ subunitCysteine mutationsTryptophan fluorescenceDwell stateDisulfide bondsEnergetic functionEnergy metabolismCatalytic siteSynthaseCatalytic dwellAffinity changesATPEnzymeAffinityConformationSubunitsMutationsSites
2020
Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB.
Artim SC, Kiyatkin A, Lemmon MA. Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB. Biochemical Journal 2020, 477: 4053-4070. PMID: 33043964, PMCID: PMC7606831, DOI: 10.1042/bcj20200695.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain-Derived Neurotrophic FactorCatalytic DomainCell DifferentiationCell ProliferationGene Knockdown TechniquesKineticsMutationNerve Growth FactorsNerve Tissue ProteinsNeuroblastomaPC12 CellsPhosphorylationProtein DomainsRatsReceptor, trkAReceptor, trkBReceptors, Growth FactorRecombinant ProteinsRNA, Small InterferingSignal TransductionCyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease
Zhang C, Balbo B, Ma M, Zhao J, Tian X, Kluger Y, Somlo S. Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2020, 32: 41-51. PMID: 33046531, PMCID: PMC7894654, DOI: 10.1681/asn.2020040511.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCatalytic DomainCDC2 Protein KinaseCell ProliferationCrosses, GeneticDNA ReplicationExome SequencingFemaleGene Expression ProfilingGene Expression RegulationMaleMiceMice, Inbred C57BLMice, KnockoutMutationPhenotypePolycystic Kidney, Autosomal DominantPyruvate Dehydrogenase Acetyl-Transferring KinaseRNA-SeqTranscription, GeneticTRPP Cation ChannelsConceptsAutosomal dominant polycystic kidney diseaseCyst cell proliferationPolycystic kidney diseaseKidney diseaseADPKD progressionCell proliferationModel of ADPKDCyst growthProgression of ADPKDDominant polycystic kidney diseaseDouble knockout miceCandidate pathwaysKidney functionCyst progressionMouse modelUnbiased transcriptional profilingProgressionCellular mechanismsKinase 1 activityCystic phenotypeSelective targetingKidneyConditional inactivationDouble knockoutProliferationStructural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation
Edani BH, Grabińska KA, Zhang R, Park EJ, Siciliano B, Surmacz L, Ha Y, Sessa WC. Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 20794-20802. PMID: 32817466, PMCID: PMC7456142, DOI: 10.1073/pnas.2008381117.Peer-Reviewed Original ResearchConceptsActive site tunnelProtein glycosylationAtomic resolution structuresGlycosyl carrier lipidsΑ3 helixEnzyme active sitePTase activityResolution structureActive siteEndoplasmic reticulumHomodimeric formCarrier lipidRate-limiting stepGlycosylationCrystal structureDHDDSStructural elucidationPTaseIsoprene chainPrenyltransferaseUnique insightsComplexesUnfavorable stateNgBRHomodimericVisualizing group II intron dynamics between the first and second steps of splicing
Manigrasso J, Chillón I, Genna V, Vidossich P, Somarowthu S, Pyle AM, De Vivo M, Marcia M. Visualizing group II intron dynamics between the first and second steps of splicing. Nature Communications 2020, 11: 2837. PMID: 32503992, PMCID: PMC7275048, DOI: 10.1038/s41467-020-16741-4.Peer-Reviewed Original ResearchConceptsGroup II intron splicingGroup II intronsSelf-splicing ribozymesGene-editing toolsIntron dynamicsEukaryotic spliceosomeActive site dynamicsIntron splicingRetrotransposable elementsCatalytic triadSplicingMolecular machinesConformational changesFirst residueMultiple conformationsSite dynamicsSpliceosomeIntronsStructural rearrangementsX-ray crystallographyEnzymatic assayStructural dataEnzymatic strategyFunctional dataActive siteFlexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation
Bhattacharyya M, Lee YK, Muratcioglu S, Qiu B, Nyayapati P, Schulman H, Groves JT, Kuriyan J. Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation. ELife 2020, 9: e53670. PMID: 32149607, PMCID: PMC7141811, DOI: 10.7554/elife.53670.Peer-Reviewed Original ResearchConceptsInhibitory autophosphorylationResidue linkerDependent protein kinase IISingle-molecule assaysMammalian cell expressionProtein kinase IICaMKII variantsShort linkerTransphosphorylation ratesKinase domainCaMKII holoenzymeKinase IIAutophosphorylationHoloenzymeFlexible linkerPrincipal isoformCalcium signalsRelative levelsIsoformsCaMKIIHuman CaCell expressionLinkerVariantsSequenceSerine phosphorylation of the small phosphoprotein ICAP1 inhibits its nuclear accumulation
Su VL, Simon B, Draheim KM, Calderwood DA. Serine phosphorylation of the small phosphoprotein ICAP1 inhibits its nuclear accumulation. Journal Of Biological Chemistry 2020, 295: 3269-3284. PMID: 32005669, PMCID: PMC7062153, DOI: 10.1074/jbc.ra119.009794.Peer-Reviewed Original ResearchConceptsIntegrin cytoplasmic domain-associated protein-1N-terminal regionNuclear accumulationP21-activated kinase 4Ser-10Nuclear roleSerine phosphorylationNuclear localizationPhosphorylation-mimicking substitutionsNuclear localization signalCell-cell junctionsSer-25Localization signalKRIT1 functionThreonine residuesAdaptor proteinKRIT1 lossSubcellular localizationNeurovascular dysplasiaBlood vessel integrityVascular developmentKinase 4Cultured cellsPhosphorylationProtein 1
2019
Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair
Ruetz M, Campanello GC, Purchal M, Shen H, McDevitt L, Gouda H, Wakabayashi S, Zhu J, Rubin EJ, Warncke K, Mootha VK, Koutmos M, Banerjee R. Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair. Science 2019, 366: 589-593. PMID: 31672889, PMCID: PMC7070230, DOI: 10.1126/science.aay0934.Peer-Reviewed Original ResearchMeSH KeywordsBiocatalysisCatalytic DomainCoenzyme ACrystallography, X-RayDeoxyadenosinesElectron Spin Resonance SpectroscopyHumansHydrogen BondingMacrophagesMethylmalonyl-CoA MutaseModels, MolecularMycobacterium tuberculosisPropionatesProtein ConformationProtein MultimerizationProtein SubunitsSuccinatesVitamin B 12The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences
Sun X, Su VL, Calderwood DA. The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences. Journal Of Biological Chemistry 2019, 294: 14319-14332. PMID: 31391252, PMCID: PMC6768646, DOI: 10.1074/jbc.ra119.007692.Peer-Reviewed Original ResearchConceptsCell-cell contactCell-cell junctionsPolybasic sequenceP21-activated kinaseSmall GTPases RacVariable regionsCell-cell boundariesPAK regulationDomain organizationCdc42 bindingAdhesion dynamicsCRIB domainGTPases RacSubcellular localizationTruncation mutantsKinase domainKinase effectorsCellular signalsExtensive similaritySequence regionsPAK1Cell adhesionCdc42PAKKinase
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