2024
Structure 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 InternalizationDesign of soluble HIV-1 envelope trimers free of covalent gp120-gp41 bonds with prevalent native-like conformation
Zhang P, Gorman J, Tsybovsky Y, Lu M, Liu Q, Gopan V, Singh M, Lin Y, Miao H, Seo Y, Kwon A, Olia A, Chuang G, Geng H, Lai Y, Zhou T, Mascola J, Mothes W, Kwong P, Lusso P. Design of soluble HIV-1 envelope trimers free of covalent gp120-gp41 bonds with prevalent native-like conformation. Cell Reports 2024, 43: 114518. PMID: 39028623, PMCID: PMC11459465, DOI: 10.1016/j.celrep.2024.114518.Peer-Reviewed Original ResearchProof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid
Papini C, Ullah I, Ranjan A, Zhang S, Wu Q, Spasov K, Zhang C, Mothes W, Crawford J, Lindenbach B, Uchil P, Kumar P, Jorgensen W, Anderson K. Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2320713121. PMID: 38621119, PMCID: PMC11046628, DOI: 10.1073/pnas.2320713121.Peer-Reviewed Original ResearchConceptsDirect-acting antiviralsSARS-CoV-2Lack of off-target effectsIn vitro pharmacological profileTreatment of patientsDevelopment of severe symptomsPharmacological propertiesDrug-drug interactionsSARS-CoV-2 infectionProof-of-concept studySARS-CoV-2 M<sup>pro</sup>.Combination regimenImmunocompromised patientsLead compoundsSARS-CoV-2 main proteaseOral doseActive drugTreat infectionsPharmacological profileSARS-CoV-2 MPotential preclinical candidateOff-target effectsPatientsComplete recoveryCapsule formulationEpistatic pathways can drive HIV-1 escape from integrase strand transfer inhibitors
Hikichi Y, Grover J, Schäfer A, Mothes W, Freed E. Epistatic pathways can drive HIV-1 escape from integrase strand transfer inhibitors. Science Advances 2024, 10: eadn0042. PMID: 38427738, PMCID: PMC10906922, DOI: 10.1126/sciadv.adn0042.Peer-Reviewed Original ResearchConceptsIntegrase strand transfer inhibitorsClasses of antiretroviralsHuman immunodeficiency virusStrand transfer inhibitorsHIV-1Env mutationsTransfer inhibitorsIntegrase strand transfer inhibitor dolutegravirHIV-1 escapeResistance to dolutegravirResistance to antiretroviralsAbsence of resistance mutationsClasses of drugsCell-cell transferVirological failureImmunodeficiency virusResistance mutationsGene mutationsEnvelope glycoproteinAntiretroviralsEnvResistance mechanismsDolutegravirMutationsIntegrase
2023
HIV-1 Env trimers asymmetrically engage CD4 receptors in membranes
Li W, Qin Z, Nand E, Grunst M, Grover J, Bess J, Lifson J, Zwick M, Tagare H, Uchil P, Mothes W. HIV-1 Env trimers asymmetrically engage CD4 receptors in membranes. Nature 2023, 623: 1026-1033. PMID: 37993716, PMCID: PMC10686830, DOI: 10.1038/s41586-023-06762-6.Peer-Reviewed Original ResearchConceptsHIV-1 Env trimersCD4 moleculeHuman immunodeficiency virus-1 (HIV-1) infectionEnv trimersAntibody-mediated immune responsesEnv-CD4 interactionVirus-1 infectionVaccine immunogen designViral envelope glycoproteinsHIV-1Immune responseCD4 receptorImmunogen designEnvelope glycoproteinVirus-like particlesCD4EnvHost cell membraneAntiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
Leonhardt S, Purdy M, Grover J, Yang Z, Poulos S, McIntire W, Tatham E, Erramilli S, Nosol K, Lai K, Ding S, Lu M, Uchil P, Finzi A, Rein A, Kossiakoff A, Mothes W, Yeager M. Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry. Nature Communications 2023, 14: 4368. PMID: 37474505, PMCID: PMC10359404, DOI: 10.1038/s41467-023-39262-2.Peer-Reviewed Original ResearchPLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factors
2019
In vivo Imaging-Driven Approaches to Study Virus Dissemination and Pathogenesis
Uchil PD, Haugh KA, Pi R, Mothes W. In vivo Imaging-Driven Approaches to Study Virus Dissemination and Pathogenesis. Annual Review Of Virology 2019, 6: 1-24. PMID: 31283440, PMCID: PMC7217087, DOI: 10.1146/annurev-virology-101416-041429.Peer-Reviewed Original ResearchAssociating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET
Lu M, Ma X, Castillo-Menendez LR, Gorman J, Alsahafi N, Ermel U, Terry DS, Chambers M, Peng D, Zhang B, Zhou T, Reichard N, Wang K, Grover JR, Carman BP, Gardner MR, Nikić-Spiegel I, Sugawara A, Arthos J, Lemke EA, Smith AB, Farzan M, Abrams C, Munro JB, McDermott AB, Finzi A, Kwong PD, Blanchard SC, Sodroski JG, Mothes W. Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET. Nature 2019, 568: 415-419. PMID: 30971821, PMCID: PMC6655592, DOI: 10.1038/s41586-019-1101-y.Peer-Reviewed Original ResearchConceptsSingle-molecule fluorescence resonance energy transferCryo-electron microscopy studiesHigh-resolution structuresFluorescence resonance energy transferState 1 conformationProline substitutionConformational statesResonance energy transferDisulfide bondsCell entryIntermediate conformationsReceptor moleculesGlycoprotein structureStructural studiesIntact virionsViral EnvCD4 receptor moleculeIntact virusConformationState 2TrimerState 1
2018
HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations
Ma X, Lu M, Gorman J, Terry DS, Hong X, Zhou Z, Zhao H, Altman RB, Arthos J, Blanchard SC, Kwong PD, Munro JB, Mothes W. HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations. ELife 2018, 7: e34271. PMID: 29561264, PMCID: PMC5896952, DOI: 10.7554/elife.34271.Peer-Reviewed Original Research
2015
Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection
Sewald X, Ladinsky MS, Uchil PD, Beloor J, Pi R, Herrmann C, Motamedi N, Murooka TT, Brehm MA, Greiner DL, Shultz LD, Mempel TR, Bjorkman PJ, Kumar P, Mothes W. Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection. Science 2015, 350: 563-567. PMID: 26429886, PMCID: PMC4651917, DOI: 10.1126/science.aab2749.Peer-Reviewed Original ResearchConceptsHuman immunodeficiency virusLymph nodesMurine leukemia virusCD169/SiglecSecondary lymphoid tissuesPermissive lymphocytesDendritic cellsImmunodeficiency virusSynaptic contactsLymphoid tissueRobust infectionVirological synapsesI-type lectinsRetroviral spreadViral spreadUninfected cellsInfectionLeukemia virusVirusMacrophagesCellsRetrovirusesCell-cell contactCD169LymphocytesCrystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env
Do Kwon Y, Pancera M, Acharya P, Georgiev I, Crooks E, Gorman J, Joyce M, Guttman M, Ma X, Narpala S, Soto C, Terry D, Yang Y, Zhou T, Ahlsen G, Bailer R, Chambers M, Chuang G, Doria-Rose N, Druz A, Hallen M, Harned A, Kirys T, Louder M, O'Dell S, Ofek G, Osawa K, Prabhakaran M, Sastry M, Stewart-Jones G, Stuckey J, Thomas P, Tittley T, Williams C, Zhang B, Zhao H, Zhou Z, Donald B, Lee L, Zolla-Pazner S, Baxa U, Schön A, Freire E, Shapiro L, Lee K, Arthos J, Munro J, Blanchard S, Mothes W, Binley J, McDermott A, Mascola J, Kwong P. Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Nature Structural & Molecular Biology 2015, 22: 522-531. PMID: 26098315, PMCID: PMC4706170, DOI: 10.1038/nsmb.3051.Peer-Reviewed Original Research
2014
Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions
Munro JB, Gorman J, Ma X, Zhou Z, Arthos J, Burton DR, Koff WC, Courter JR, Smith AB, Kwong PD, Blanchard SC, Mothes W. Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. Science 2014, 346: 759-763. PMID: 25298114, PMCID: PMC4304640, DOI: 10.1126/science.1254426.Peer-Reviewed Original Research
2000
Secreted cathepsin L generates endostatin from collagen XVIII
Felbor U, Dreier L, Bryant R, Ploegh H, Olsen B, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. The EMBO Journal 2000, 19: 1187-1194. PMID: 10716919, PMCID: PMC305660, DOI: 10.1093/emboj/19.6.1187.Peer-Reviewed Original ResearchAnimalsCathepsin LCathepsinsCell LineCollagenCollagen Type XVIIICulture Media, ConditionedCysteine EndopeptidasesEndopeptidasesEndostatinsEndothelium, VascularEnzyme PrecursorsHumansHydrogen-Ion ConcentrationKineticsMatrix MetalloproteinasesMiceModels, BiologicalMolecular WeightPeptide FragmentsProtein Processing, Post-TranslationalProtein Structure, TertiaryRecombinant Fusion ProteinsTumor Cells, Cultured
1996
Sec6l-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction
Wiertz E, Tortorella D, Bogyo M, Yu J, Mothes W, Jones T, Rapoport T, Ploegh H. Sec6l-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 1996, 384: 432-438. PMID: 8945469, DOI: 10.1038/384432a0.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateBiological Transport, ActiveCell LineCysteine EndopeptidasesCytomegalovirusCytosolEndoplasmic ReticulumGlycosylationHistocompatibility Antigens Class IHumansMembrane ProteinsMultienzyme ComplexesProteasome Endopeptidase ComplexProtein FoldingSEC Translocation ChannelsViral Proteins