2025
The C2 domain augments Ras GTPase-activating protein catalytic activity
Paul M, Chen D, Vish K, Lartey N, Hughes E, Freeman Z, Saunders T, Stiegler A, King P, Boggon T. The C2 domain augments Ras GTPase-activating protein catalytic activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2418433122. PMID: 39899710, PMCID: PMC11831179, DOI: 10.1073/pnas.2418433122.Peer-Reviewed Original ResearchConceptsGTPase-activating proteinC2 domainActivity of GTPase-activating proteinGTPase-activating protein domainProtein catalytic activityDomain in vitroAllosteric lobeRas GTPasesSequence conservationGTPase activityAlphaFold modelsRasGAPSignaling defectsRasMutationsCatalytic activityConstitutive disruptionCatalytic advantageGTPaseAlphaFoldDomainGenesSynGAPProteinSequenceStructural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2
Koide E, Pietz H, Beltran J, Chen J. Structural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2. Nature Communications 2025, 16: 484. PMID: 39779684, PMCID: PMC11711199, DOI: 10.1038/s41467-024-55810-w.Peer-Reviewed Original ResearchConceptsAutoinhibited stateR domainPost-translocation stateSubstrate-binding sitePre-translocation stateATP-binding siteProtein 2Nucleotide-binding domain 2Cryogenic electron microscopyStructural basisDiverse array of compoundsDomain 2Cryo-EMRegulation mechanismChemotherapeutic resistanceConformational changesMultidrug resistanceArray of compoundsDiverse arrayConformational statesLiver homeostasisMultidrug resistance-associated protein 2Initial transportSubstrateCytosol
2024
Structures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes
Zhou Y, Stevis P, Cao J, Ehrlich G, Jones J, Rafique A, Sleeman M, Olson W, Franklin M. Structures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes. Nature Communications 2024, 15: 9776. PMID: 39532904, PMCID: PMC11557873, DOI: 10.1038/s41467-024-54124-1.Peer-Reviewed Original ResearchConceptsLeukemia inhibitory factor receptorOncostatin MExtracellular assemblyReceptor complexOSM receptorOncostatin M signalingOncostatin M receptorJuxtamembrane domainGp130 bindingCryogenic electron microscopyStructural basisGlycoprotein 130Cryo-EMFamily cytokinesBiological eventsGp130Therapeutic targetComplex formationFactor receptorType IMouse typesReceptorsAssemblyJuxtamembraneMutagenesisHIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration
Jang S, Bedwell G, Singh S, Yu H, Arnarson B, Singh P, Radhakrishnan R, Douglas A, Ingram Z, Freniere C, Akkermans O, Sarafianos S, Ambrose Z, Xiong Y, Anekal P, Llopis P, KewalRamani V, Francis A, Engelman A. HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration. Nucleic Acids Research 2024, 52: 11060-11082. PMID: 39258548, PMCID: PMC11472059, DOI: 10.1093/nar/gkae769.Peer-Reviewed Original ResearchConceptsHIV-1 infectionHIV-1Viral DNA integrationCPSF6 knockout cellsActivity in vitroHIV-1 pathogenesisHIV-1 integrationDNA integrityLiquid-liquid phase separationViral infectionNuclear specklesInfectionCapsids in vitroCPSF6NS depletionNuclear entryCapsid bindingCapsid-binding proteinKnockout cellsBinding proteinSR proteinsNuclear rimCo-aggregationDisordered regionsStructure and inhibition of SARS-CoV-2 spike refolding in membranes
Grunst M, Qin Z, Dodero-Rojas E, Ding S, Prévost J, Chen Y, Hu Y, Pazgier M, Wu S, Xie X, Finzi A, Onuchic J, Whitford P, Mothes W, Li W. Structure and inhibition of SARS-CoV-2 spike refolding in membranes. Science 2024, 385: 757-765. PMID: 39146425, PMCID: PMC11449073, DOI: 10.1126/science.adn5658.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2Antibodies, NeutralizingAntibodies, ViralBetacoronavirusCell MembraneCOVID-19Cryoelectron MicroscopyElectron Microscope TomographyHumansMolecular Dynamics SimulationPeptidyl-Dipeptidase AProtein DomainsProtein MultimerizationProtein RefoldingSARS-CoV-2Spike Glycoprotein, CoronavirusVirus Internalization
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 targetComplexesCECR2ChromatinBromodomainsBPTFFamilyNanoBRETBacteria require phase separation for fitness in the mammalian gut
Krypotou E, Townsend G, Gao X, Tachiyama S, Liu J, Pokorzynski N, Goodman A, Groisman E. Bacteria require phase separation for fitness in the mammalian gut. Science 2023, 379: 1149-1156. PMID: 36927025, PMCID: PMC10148683, DOI: 10.1126/science.abn7229.Peer-Reviewed Original ResearchConceptsMammalian gutTranscription termination factor RhoTermination factor RhoGene regulationTranscription terminationMechanisms bacteriaBacteria interactionsHuman commensalValuable targetBacteriaRhoGut microbiotaFitnessNovel clinical applicationsTherapeutic manipulationGutHuman healthCommensalRegulation
2022
A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain
Bai P, Yan L, Bagdasarian F, Wilks M, Wey H, Wang C. A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain. Chemical Communications 2022, 58: 9654-9657. PMID: 35943085, PMCID: PMC9618257, DOI: 10.1039/d2cc03785h.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Cycle ProteinsMiceNuclear ProteinsPositron-Emission TomographyProtein DomainsTranscription FactorsConceptsPositron emission tomography imaging studiesPositron emission tomographyNon-human primatesModerate brain uptakeImaging studiesBrain uptakePositron emission tomography imaging probeEmission tomographyBrain permeabilityBrainBromodomains of BRD2Clinical translationExtra-terminal domainTranslational potentialInhibitor developmentNeurological diseasesBinding specificityNew mechanism of chromatin compartmentalization by BRD2
Cheng Y, Wang S. New mechanism of chromatin compartmentalization by BRD2. Trends In Genetics 2022, 38: 1197-1198. PMID: 35811175, DOI: 10.1016/j.tig.2022.06.016.Peer-Reviewed Original ResearchSARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies
Reincke S, Yuan M, Kornau H, Corman V, van Hoof S, Sánchez-Sendin E, Ramberger M, Yu W, Hua Y, Tien H, Schmidt M, Schwarz T, Jeworowski L, Brandl S, Rasmussen H, Homeyer M, Stöffler L, Barner M, Kunkel D, Huo S, Horler J, von Wardenburg N, Kroidl I, Eser T, Wieser A, Geldmacher C, Hoelscher M, Gänzer H, Weiss G, Schmitz D, Drosten C, Prüss H, Wilson I, Kreye J. SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies. Science 2022, 375: eabm5835. PMID: 35076281, PMCID: PMC8939768, DOI: 10.1126/science.abm5835.Peer-Reviewed Original ResearchConceptsCross-reactive antibodiesReceptor-binding domain antibodiesMajor antibody classCOVID-19 patientsSARS-CoV-2Next-generation vaccinesInfection elicitsVaccinated individualsAntibody responseAntibody classAntigenic driftWild-type virusPatientsBeta variantAntibodiesClonotypesDomain antibodiesVaccineMutationsSerumSingle particle cryo-EM structure of the outer hair cell motor protein prestin
Butan C, Song Q, Bai JP, Tan WJT, Navaratnam D, Santos-Sacchi J. Single particle cryo-EM structure of the outer hair cell motor protein prestin. Nature Communications 2022, 13: 290. PMID: 35022426, PMCID: PMC8755724, DOI: 10.1038/s41467-021-27915-z.Peer-Reviewed Original ResearchConceptsTransmembrane domainProtein prestinSingle-particle cryo-EM structuresAnti-sigma factor antagonist domainOuter hair cell motor protein prestinCryo-EM structureCryo-electron microscopyMotor protein prestinSLC26 family membersSulfate transportersTransmembrane segmentsPrestin functionÅ resolutionPrestinOHC electromotilityOpen stateCochlear amplificationPutative mechanismsFamily membersDomainRepeatsSLC26A9TransportersMutationsElectromotilityHigh cell surface expression and peptide binding affinity of HLA-DQA1*05:03, a susceptible allele of neuromyelitis optica spectrum disorders (NMOSD)
Beppu S, Kinoshita M, Wilamowski J, Suenaga T, Yasumizu Y, Ogawa K, Ishikura T, Tada S, Koda T, Murata H, Shiraishi N, Sugiyama Y, Kihara K, Sugimoto T, Arase H, Standley D, Okuno T, Mochizuki H. High cell surface expression and peptide binding affinity of HLA-DQA1*05:03, a susceptible allele of neuromyelitis optica spectrum disorders (NMOSD). Scientific Reports 2022, 12: 106. PMID: 34997058, PMCID: PMC8742014, DOI: 10.1038/s41598-021-04074-1.Peer-Reviewed Original ResearchConceptsNeuromyelitis optica spectrum disorderPeptide major histocompatibility complexDevelopment of neuromyelitis optica spectrum disorderAnti-aquaporin-4HLA-DQA1Associated with neuromyelitis optica spectrum disordersHigh cell surface expressionJapanese patient cohortPresence of pathogenic autoantibodiesCell surface expression levelsRelapsing autoimmune diseaseHLA-DQA1 allelesCell surface expressionSurface expression levelsAQP4 peptidesMajor histocompatibility complexAnti-aquaporinPathogenic autoantibodiesHLA-DQPatient cohortAutoimmune diseasesPathogenic roleSurface expressionIn silico 3D structure modelingHistocompatibility complex
2021
Structural basis for ligand reception by anaplastic lymphoma kinase
Li T, Stayrook SE, Tsutsui Y, Zhang J, Wang Y, Li H, Proffitt A, Krimmer SG, Ahmed M, Belliveau O, Walker IX, Mudumbi KC, Suzuki Y, Lax I, Alvarado D, Lemmon MA, Schlessinger J, Klein DE. Structural basis for ligand reception by anaplastic lymphoma kinase. Nature 2021, 600: 148-152. PMID: 34819665, PMCID: PMC8639777, DOI: 10.1038/s41586-021-04141-7.Peer-Reviewed Original ResearchInhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
Kumar M, Molkentine D, Molkentine J, Bridges K, Xie T, Yang L, Hefner A, Gao M, Bahri R, Dhawan A, Frederick MJ, Seth S, Abdelhakiem M, Beadle BM, Johnson F, Wang J, Shen L, Heffernan T, Sheth A, Ferris RL, Myers JN, Pickering CR, Skinner HD. Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function. Nature Communications 2021, 12: 6340. PMID: 34732714, PMCID: PMC8566594, DOI: 10.1038/s41467-021-26570-8.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAnimalsApoptosisBiomarkers, TumorBRCA1 ProteinCell Line, TumorCREB-Binding ProteinE1A-Associated p300 ProteinGain of Function MutationHistone AcetyltransferasesHomologous RecombinationHumansMaleMice, NudeMutationNeoplasmsProtein DomainsSquamous Cell Carcinoma of Head and NeckXenograft Model Antitumor AssaysAtg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosome
Chandra S, Mannino PJ, Thaller DJ, Ader NR, King MC, Melia TJ, Lusk CP. Atg39 selectively captures inner nuclear membrane into lumenal vesicles for delivery to the autophagosome. Journal Of Cell Biology 2021, 220: e202103030. PMID: 34714326, PMCID: PMC8575018, DOI: 10.1083/jcb.202103030.Peer-Reviewed Original ResearchMeSH KeywordsAutophagosomesAutophagyAutophagy-Related ProteinsCytoplasmic VesiclesGreen Fluorescent ProteinsNuclear EnvelopeProtein DomainsReceptors, Cytoplasmic and NuclearSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsStructure-Activity RelationshipTime FactorsVacuolesVesicular Transport ProteinsConceptsInner nuclear membraneNuclear envelope lumenOuter nuclear membraneNuclear membraneSplit-GFP reporterNuclear envelope localizationINM proteinsAutophagy apparatusEnvelope localizationLumenal vesiclesLumenal domainCargo adaptorsAtg39Sequence elementsCorrelative lightVesiclesAutophagosomesMembraneNucleophagyAdaptorReporterProteinOverexpressionMotifFunctional Effects of Receptor-Binding Domain Mutations of SARS-CoV-2 B.1.351 and P.1 Variants
Bayarri-Olmos R, Jarlhelt I, Johnsen L, Hansen C, Helgstrand C, Bjelke J, Matthiesen F, Nielsen S, Iversen K, Ostrowski S, Bundgaard H, Frikke-Schmidt R, Garred P, Skjoedt M. Functional Effects of Receptor-Binding Domain Mutations of SARS-CoV-2 B.1.351 and P.1 Variants. Frontiers In Immunology 2021, 12: 757197. PMID: 34691078, PMCID: PMC8529273, DOI: 10.3389/fimmu.2021.757197.Peer-Reviewed Original ResearchInsights into the structure and RNA-binding specificity of Caenorhabditis elegans Dicer-related helicase 3 (DRH-3)
Li K, Zheng J, Wirawan M, Trinh NM, Fedorova O, Griffin PR, Pyle AM, Luo D. Insights into the structure and RNA-binding specificity of Caenorhabditis elegans Dicer-related helicase 3 (DRH-3). Nucleic Acids Research 2021, 49: 9978-9991. PMID: 34403472, PMCID: PMC8464030, DOI: 10.1093/nar/gkab712.Peer-Reviewed Original ResearchConceptsC-terminal domainN-terminal domainDRH-3RNA interferenceTandem caspase activationSimilar domain architectureEndogenous RNAi pathwaysRNA helicase familyDouble-stranded RNACARDs of RIGUnique structural dynamicsGermline developmentEvolutionary divergenceChromosome segregationRNAi pathwayCaenorhabditis elegansDomain architectureHelicase familyCaspase activationDistinct foldsRecruitment domainMolecular understandingRLR familyRNA duplexesRNASARS-CoV-2 Neutralizing Antibody Responses towards Full-Length Spike Protein and the Receptor-Binding Domain
Bayarri-Olmos R, Idorn M, Rosbjerg A, Pérez-Alós L, Hansen C, Johnsen L, Helgstrand C, Zosel F, Bjelke J, Öberg F, Søgaard M, Paludan S, Bak-Thomsen T, Jardine J, Skjoedt M, Garred P. SARS-CoV-2 Neutralizing Antibody Responses towards Full-Length Spike Protein and the Receptor-Binding Domain. The Journal Of Immunology 2021, 207: 878-887. PMID: 34301847, DOI: 10.4049/jimmunol.2100272.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2AnimalsAntibodies, MonoclonalAntibodies, NeutralizingAntibodies, ViralAntigens, ViralCoronavirus Nucleocapsid ProteinsCOVID-19COVID-19 SerotherapyCOVID-19 VaccinesEnzyme-Linked Immunosorbent AssayHumansImmunizationImmunization, PassiveImmunoglobulin AImmunoglobulin GImmunoglobulin MMiceNeutralization TestsProtein DomainsReceptors, VirusSARS-CoV-2Spike Glycoprotein, CoronavirusConceptsPlaque reduction neutralization testReceptor-binding domainReduction neutralization testNeutralization testFull-length spike proteinSARS-CoV-2 transmissionSARS-CoV-2 receptor-binding domainViral neutralization testSARS-CoV-2Levels of AbsIgG titersVaccine strategiesAntibody responsePreclinical modelsConvalescent seraImmune responseMouse modelNeutralization potencyVirus neutralizationFull spikesImmunization strategiesMurine mAbsImmunization resultsSpike proteinELISAMucinomics as the Next Frontier of Mass Spectrometry
Rangel-Angarita V, Malaker SA. Mucinomics as the Next Frontier of Mass Spectrometry. ACS Chemical Biology 2021, 16: 1866-1883. PMID: 34319686, DOI: 10.1021/acschembio.1c00384.Peer-Reviewed Original ResearchStructural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme
Liu C, Shi W, Becker ST, Schatz DG, Liu B, Yang Y. Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme. Science 2021, 373: 1142-1146. PMID: 34315827, PMCID: PMC9836006, DOI: 10.1126/science.abi9310.Peer-Reviewed Original ResearchConceptsCryo-electron microscopy structureRNA synthesisCoronavirus RNA synthesisNascent RNAMicroscopy structureVirus life cycleMismatch recognitionRNA substratesSubstrate specificityStructural basisMolecular mechanismsNonstructural proteinsMolecular determinantsProofreading enzymeReplication fidelityMismatch correctionAnalogue inhibitorsLife cycleExoribonucleaseExonsComplexesRNARational designProteinEnzyme
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