2024
Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies
Raina K, Forbes C, Stronk R, Rappi J, Eastman K, Zaware N, Yu X, Li H, Bhardwaj A, Gerritz S, Forgione M, Hundt A, King M, Posner Z, Correia A, McGovern A, Puleo D, Chenard R, Mousseau J, Vergara J, Garvin E, Macaluso J, Martin M, Bassoli K, Jones K, Garcia M, Howard K, Yaggi M, Smith L, Chen J, Mayfield A, De Leon C, Hines J, Kayser-Bricker K, Crews C. Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies. Cell Chemical Biology 2024, 31: 1490-1502.e42. PMID: 39116881, PMCID: PMC11371387, DOI: 10.1016/j.chembiol.2024.07.005.Peer-Reviewed Original ResearchProtein-protein interactionsTarget proteinsTernary complexChemical biology studiesExpressed intracellular proteinStable ternary complexAnti-proliferative responseEssential proteinsProtein proximityEffector ligandsIntracellular proteinsCDK inhibitorsTarget-expressing cellsHeterobifunctional small moleculesSmall moleculesCell survivalTumor cellsTherapeutic modalitiesProteinSelective therapySmall molecule strategiesLigandBiological studiesβ‑Amino Acids Reduce Ternary Complex Stability and Alter the Translation Elongation Mechanism
Cruz-Navarrete F, Griffin W, Chan Y, Martin M, Alejo J, Brady R, Natchiar S, Knudson I, Altman R, Schepartz A, Miller S, Blanchard S. β‑Amino Acids Reduce Ternary Complex Stability and Alter the Translation Elongation Mechanism. ACS Central Science 2024, 10: 1262-1275. PMID: 38947208, PMCID: PMC11212133, DOI: 10.1021/acscentsci.4c00314.Peer-Reviewed Original ResearchNon-natural amino acidsComplex stabilityTernary complex stabilityTemplate synthesisDetection limitEnergy transfer measurementsTernary complex formationComplex formationSingle-molecule fluorescence resonance energy transfer measurementsIn vitro detection limitTernary complexFluorescence resonance energy transfer measurementsAmino acidsMechanism of protein synthesisResonance energy transfer measurementsSynthesis of proteinsRate of translocationMRNA decodingElongation substratesStabilityElongation factorIsomersRibosome utilizationAminoacyl-tRNAStereoisomersDynamic recruitment of inhibitory complexes by CD25 controls B-cell development and selection
Sun R, Lee J, Robinson M, Kume K, Ma N, Cosgun K, Chan L, Antoshkina I, Khanduja D, Leveille E, Katz S, Vaidehi N, Müschen M. Dynamic recruitment of inhibitory complexes by CD25 controls B-cell development and selection. The Journal Of Immunology 2024, 212: 1253_4618-1253_4618. DOI: 10.4049/jimmunol.212.supp.1253.4618.Peer-Reviewed Original ResearchBCR signalingInhibitory complexInhibitory phosphatasesPositively charged tailITIM-bearing receptorsInitiation of BCR signalingNegatively charged residuesB cell developmentSH2 domainPhosphatase domainCytoplasmic tailITIM motifsGenetic studiesPhosphatase SHP1Co-IPBCR complexDynamic recruitmentIL2 receptorCell surfaceB cellsSHP1Surface-expressedTernary complexClonal expansionPhosphatase
2023
Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes
Zahid H, Costello J, Li Y, Kimbrough J, Actis M, Rankovic Z, Yan Q, Pomerantz W. Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes. ACS Chemical Biology 2023, 18: 1278-1293. PMID: 37260298, PMCID: PMC10698694, DOI: 10.1021/acschembio.2c00902.Peer-Reviewed Original ResearchConceptsChromatin Remodeling ComplexNon-BET bromodomainsRemodeling complexProtein degradationHeterobifunctional moleculesBET familyProtein targetsPyrimidine base analogsNumber of degradersDegradersOncogenic roleTernary complexExit vectorsWestern blottingProteinFirst exampleClass IChallenging targetComplexesCECR2ChromatinBromodomainsBPTFFamilyNanoBRET
2021
Structure of New Binary and Ternary DNA Polymerase Complexes From Bacteriophage RB69
Park J, Youn HS, An JY, Lee Y, Eom SH, Wang J. Structure of New Binary and Ternary DNA Polymerase Complexes From Bacteriophage RB69. Frontiers In Molecular Biosciences 2021, 8: 704813. PMID: 34869578, PMCID: PMC8639217, DOI: 10.3389/fmolb.2021.704813.Peer-Reviewed Original ResearchDivalent metal ionsMetal ionsT duplexSecond divalent metal ionSingle divalent metal ionDimeric complexCrystal structureTernary complex structureBinary complexIonsSpecific interactionsTernary complexDimeric formAdditional conformational changesComplexesInitial bindingDNA complexesConformational changesNew binaryClosed ternary complexRB69polDNTP-binding pocketStructurePolymerizationBiological relevanceModulation 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 resistanceBifunctional small molecules that mediate the degradation of extracellular proteins
Caianiello DF, Zhang M, Ray JD, Howell RA, Swartzel JC, Branham EMJ, Chirkin E, Sabbasani VR, Gong AZ, McDonald DM, Muthusamy V, Spiegel DA. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nature Chemical Biology 2021, 17: 947-953. PMID: 34413525, DOI: 10.1038/s41589-021-00851-1.Peer-Reviewed Original ResearchConceptsExtracellular proteinsTarget proteinsUbiquitin-proteasome systemBifunctional small moleculesSynthetic moleculesProtein degradationIntracellular proteinsProinflammatory cytokine proteinProteinLysosomal proteasesTernary complexSmall moleculesPromising therapeutic strategyCytokine proteinsTherapeutic strategiesMoleculesDegradationProteaseDisease treatmentExperimental evidence
2018
An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
Lino Cardenas CL, Kessinger CW, Cheng Y, MacDonald C, MacGillivray T, Ghoshhajra B, Huleihel L, Nuri S, Yeri AS, Jaffer FA, Kaminski N, Ellinor P, Weintraub NL, Malhotra R, Isselbacher EM, Lindsay ME. An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nature Communications 2018, 9: 1009. PMID: 29520069, PMCID: PMC5843596, DOI: 10.1038/s41467-018-03394-7.Peer-Reviewed Original ResearchMeSH KeywordsActomyosinAnimalsAortaAortic Aneurysm, ThoracicCell LineCell NucleusChromatinDisease Models, AnimalDNA HelicasesDNA MethylationFemaleFluorescent Antibody TechniqueHistone DeacetylasesHistonesHumansMaleMiceMice, KnockoutMuscle, Smooth, VascularMutationMyocytes, Smooth MuscleNuclear ProteinsPhenotypePrimary Cell CultureRepressor ProteinsRNA InterferenceRNA, Long NoncodingRNA, Small InterferingSignal TransductionTranscription FactorsTransforming Growth Factor betaConceptsChromatin-remodeling enzyme BRG1Contractile protein gene expressionProtein gene expressionLong noncoding RNA MALAT1Noncoding RNA MALAT1Bind chromatinTGF-β signalingTrimethylation modificationActomyosin cytoskeletonEpigenetic pathwaysContractile protein expressionGene expressionSimilar phenotypeRNA MALAT1Ternary complexBRG1HDAC9VSMC dysfunctionAortic aneurysmCytoskeletonProtein expressionPotential common mechanismsCommon mechanismSmooth muscle dysfunctionMutations
2015
Structural requirements for protein-catalyzed annealing of U4 and U6 RNAs during di-snRNP assembly
Didychuk A, Montemayor E, Brow D, Butcher S. Structural requirements for protein-catalyzed annealing of U4 and U6 RNAs during di-snRNP assembly. Nucleic Acids Research 2015, 44: 1398-1410. PMID: 26673715, PMCID: PMC4756825, DOI: 10.1093/nar/gkv1374.Peer-Reviewed Original ResearchMeSH KeywordsBase SequenceBinding, CompetitiveKineticsModels, MolecularMolecular Sequence DataMutationNucleic Acid ConformationProtein BindingProtein Structure, TertiaryRibonucleoprotein, U4-U6 Small NuclearRibonucleoproteins, Small NuclearRNA, FungalRNA, Small NuclearSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsConceptsU6 RNADi-snRNPRemodeling of RNA structureAnnealing in vitroTri-snRNP complexLarge-scale remodelingStable ternary complexRNA bindingRNA structureRibonucleoprotein complexU6 snRNPU6 snRNABase pairsPrp24RNATernary complexU4/U6Electropositive characterRate enhancementAssemblyStructural requirementsSnRNASnRNPLsm2Annealing rateSmall molecule‐induced catalytic ubiquitination of non‐natural substrates
Bondeson D, Pancevac C, Kruidenier L, Carter P, Churcher I, Crews C. Small molecule‐induced catalytic ubiquitination of non‐natural substrates. The FASEB Journal 2015, 29 DOI: 10.1096/fasebj.29.1_supplement.573.43.Peer-Reviewed Original Research
2013
Conformational landscapes of DNA polymerase I and mutator derivatives establish fidelity checkpoints for nucleotide insertion
Hohlbein J, Aigrain L, Craggs T, Bermek O, Potapova O, Shoolizadeh P, Grindley N, Joyce C, Kapanidis A. Conformational landscapes of DNA polymerase I and mutator derivatives establish fidelity checkpoints for nucleotide insertion. Nature Communications 2013, 4: 2131. PMID: 23831915, PMCID: PMC3715850, DOI: 10.1038/ncomms3131.Peer-Reviewed Original ResearchConceptsClosed conformationDNA polymerase IIncorrect nucleotidesPolymerase ITernary complexSingle-molecule FRETActive site side chainsNucleotide selectionMutator phenotypeFidelity checkpointPrimary checkpointPhosphoryl transferFidelity mutantsConformational changesConformational landscapeDNA polymeraseNucleotide insertionConformational transitionDNA synthesisFRET valuesNucleotidesFree energy landscapeReduced affinityCheckpointConformationDevelopment of modified siRNA molecules incorporating 5-fluoro-2′-deoxyuridine residues to enhance cytotoxicity
Wu SY, Chen TM, Gmeiner WH, Chu E, Schmitz JC. Development of modified siRNA molecules incorporating 5-fluoro-2′-deoxyuridine residues to enhance cytotoxicity. Nucleic Acids Research 2013, 41: 4650-4659. PMID: 23449220, PMCID: PMC3632118, DOI: 10.1093/nar/gkt120.Peer-Reviewed Original ResearchConceptsTS proteinMultiple DNA damage repairCovalent inhibitory ternary complexNovel drug development approachDNA damage repairInhibitory ternary complexRNA stabilityDamage repairApoptotic pathwayHuman diseasesWatson-Crick base pairingPrecise fateSiRNAsControl siRNAsBase pairingTernary complexRNA expressionThymidylate synthaseMessenger RNA expressionDrug development approachesCytotoxic nucleosidesInhibitor compoundsNucleotidesSiRNAProtein
2012
Bidentate and tridentate metal‐ion coordination states within ternary complexes of RB69 DNA polymerase
Xia S, Eom SH, Konigsberg WH, Wang J. Bidentate and tridentate metal‐ion coordination states within ternary complexes of RB69 DNA polymerase. Protein Science 2012, 21: 447-451. PMID: 22238207, PMCID: PMC3375444, DOI: 10.1002/pro.2026.Peer-Reviewed Original ResearchConceptsCoordination complexesMetal ionsCoordination stateSecond metal ionMetal ion coordinationDivalent metal ionsTernary complexTridentate coordinationBond formationPhosphorus atomActive siteRelevant conformationsStructural studiesSelectivity mechanismIonsTriphosphate tailComplexesRB69 DNA polymeraseÅ resolutionBase selectivityGround stateSubstrate alignmentPolymerase active siteCatalysisCoordination
2011
Nucleosome Disruption by DNA Ligase III-XRCC1 Promotes Efficient Base Excision Repair
Odell ID, Barbour JE, Murphy DL, Della-Maria JA, Sweasy JB, Tomkinson AE, Wallace SS, Pederson DS. Nucleosome Disruption by DNA Ligase III-XRCC1 Promotes Efficient Base Excision Repair. Molecular And Cellular Biology 2011, 31: 4623-4632. PMID: 21930793, PMCID: PMC3209256, DOI: 10.1128/mcb.05715-11.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDeoxyribonuclease (Pyrimidine Dimer)DNADNA DamageDNA GlycosylasesDNA Ligase ATPDNA LigasesDNA Polymerase betaDNA RepairDNA-(Apurinic or Apyrimidinic Site) LyaseDNA-Binding ProteinsHumansLytechinusNucleosomesPoly-ADP-Ribose Binding ProteinsReactive Oxygen SpeciesX-ray Repair Cross Complementing Protein 1XenopusXenopus ProteinsConceptsBase excision repairNucleosome disruptionApurinic endonucleaseExcision repairEfficient base excision repairNucleated human cellsDNA polymerase βNucleosome substratesRibosomal DNASingle base gapHuman cellsNucleosomesDNA ligasePolymerase βPol βRate-limiting stepHNTH1Ternary complexDNAUnique roleChromatinLigaseDisruptionEndonucleaseLesions formStructural Insights into Complete Metal Ion Coordination from Ternary Complexes of B Family RB69 DNA Polymerase
Xia S, Wang M, Blaha G, Konigsberg WH, Wang J. Structural Insights into Complete Metal Ion Coordination from Ternary Complexes of B Family RB69 DNA Polymerase. Biochemistry 2011, 50: 9114-9124. PMID: 21923197, PMCID: PMC3760225, DOI: 10.1021/bi201260h.Peer-Reviewed Original ResearchConceptsMetal ionsBond formationHydroxyl groupsCoordination bond lengthsMetal ion coordinationΑ-phosphateB-siteTernary complexMetal ion ACoordination complexesIon coordinationBond lengthsCoordination octahedraIon APhosphorus atomIonic radiusSimultaneous coordinationPhosphodiester bond formationIonsNucleotidyl transferStructural insightsComplexesPyrophosphate productVariation in Mutation Rates Caused by RB69pol Fidelity Mutants Can Be Rationalized on the Basis of Their Kinetic Behavior and Crystal Structures
Xia S, Wang M, Lee HR, Sinha A, Blaha G, Christian T, Wang J, Konigsberg W. Variation in Mutation Rates Caused by RB69pol Fidelity Mutants Can Be Rationalized on the Basis of Their Kinetic Behavior and Crystal Structures. Journal Of Molecular Biology 2011, 406: 558-570. PMID: 21216248, PMCID: PMC3059800, DOI: 10.1016/j.jmb.2010.12.033.Peer-Reviewed Original ResearchConceptsDouble mutantMutation rateAmino acid residuesRB69 DNA polymeraseSingle mutantsMutable sequencesPocket mutantsMutantsAcid residuesState kinetic parametersPrimer extensionT4 phageFidelity mutantsNucleotide residuesIncoming dNTPsDNA polymeraseReversion assayTernary complexComplementary strandCrystal structureResiduesBase selectivityPocketPolymeraseMisincorporation
2009
Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer
Murelli RP, Zhang AX, Michel J, Jorgensen WL, Spiegel DA. Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer. Journal Of The American Chemical Society 2009, 131: 17090-17092. PMID: 19888723, PMCID: PMC2794306, DOI: 10.1021/ja906844e.Peer-Reviewed Original ResearchConceptsSmall moleculesFundamental chemical principlesBifunctional small moleculesProstate-specific membrane antigenProstate cancer cellsProstate cancerChemical principlesBiological evaluationCrystallographic dataMoleculesAmerican male populationTernary complexLNCaP human prostate cancer cellsCancer cellsHuman effector cellsHuman prostate cancer cellsCancer-related deathAntibody-dependent killingClasses of antibodiesHigh therapeutic potentialNovel classAntibody-recruiting moleculesHuman immune systemAnti-DNP antibodiesEffector cellsSuppression of RhoG activity is mediated by a syndecan 4–synectin–RhoGDI1 complex and is reversed by PKCα in a Rac1 activation pathway
Elfenbein A, Rhodes JM, Meller J, Schwartz MA, Matsuda M, Simons M. Suppression of RhoG activity is mediated by a syndecan 4–synectin–RhoGDI1 complex and is reversed by PKCα in a Rac1 activation pathway. Journal Of Cell Biology 2009, 186: 75-83. PMID: 19581409, PMCID: PMC2712988, DOI: 10.1083/jcb.200810179.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsCluster AnalysisEnzyme ActivationFibroblast Growth Factor 2GTP PhosphohydrolasesGuanine Nucleotide Dissociation InhibitorsHeLa CellsHumansMiceMice, KnockoutModels, BiologicalPhosphorylationPhosphoserineProtein Kinase C-alpharac1 GTP-Binding ProteinRatsrho GTP-Binding Proteinsrho-Specific Guanine Nucleotide Dissociation InhibitorsSyndecan-4ConceptsFibroblast growth factor-2Polarized activationRac1 activationSmall guanosine triphosphatase Rac1Activation pathwayProtein complexesRac activationPlasma membranePhysiological defectsSyndecan-4RhoGDI1Major regulatorInactive stateGrowth factor 2RhoGRhoG activityProteoglycan receptorsEndothelial migrationTernary complexFactor 2Genetic deletionSynectinRac1PKCalphaActivationKinetic Analysis of the Guanine Nucleotide Exchange Activity of TRAPP, a Multimeric Ypt1p Exchange Factor
Chin HF, Cai Y, Menon S, Ferro-Novick S, Reinisch KM, De La Cruz EM. Kinetic Analysis of the Guanine Nucleotide Exchange Activity of TRAPP, a Multimeric Ypt1p Exchange Factor. Journal Of Molecular Biology 2009, 389: 275-288. PMID: 19361519, PMCID: PMC2770256, DOI: 10.1016/j.jmb.2009.03.068.Peer-Reviewed Original ResearchConceptsMembrane trafficExchange factorGuanine nucleotide exchange activityRab GTPase Ypt1pLarge multimeric assembliesNucleotide exchange activityThermodynamic linkage analysisWeak thermodynamic couplingTRAPP complexesStable ternary complexTRAPP subunitsGEF activityYpt1pNucleotide bindingMultimeric assembliesNucleotide exchangeNucleotide dissociationNucleotide affinityLinkage analysisIndependent pathwaysGEF systemTernary complexExchange activityTRAPPOverall net changeStructures of RB69 DNA polymerase ternary complexes reveal multiple modes of metal ion coordination to correct incoming dNTPs
Wang M, Konigsberg W, Steitz T, Wang J. Structures of RB69 DNA polymerase ternary complexes reveal multiple modes of metal ion coordination to correct incoming dNTPs. The FASEB Journal 2009, 23: 482.1-482.1. DOI: 10.1096/fasebj.23.1_supplement.482.1.Peer-Reviewed Original Research
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