Featured Publications
Sarecycline inhibits protein translation in Cutibacterium acnes 70S ribosome using a two-site mechanism
Lomakin I, Devarkar S, Patel S, Grada A, Bunick C. Sarecycline inhibits protein translation in Cutibacterium acnes 70S ribosome using a two-site mechanism. Nucleic Acids Research 2023, 51: 2915-2930. PMID: 36864821, PMCID: PMC10085706, DOI: 10.1093/nar/gkad103.Peer-Reviewed Original ResearchHuman keratin 1/10‐1B tetramer structures reveal a knob‐pocket mechanism in intermediate filament assembly
Eldirany SA, Ho M, Hinbest AJ, Lomakin IB, Bunick CG. Human keratin 1/10‐1B tetramer structures reveal a knob‐pocket mechanism in intermediate filament assembly. The EMBO Journal 2019, 38: embj2018100741. PMID: 31036554, PMCID: PMC6545558, DOI: 10.15252/embj.2018100741.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionCircular DichroismCrystallography, X-RayCytoskeletonDynamic Light ScatteringHumansHydrophobic and Hydrophilic InteractionsIntermediate Filament ProteinsKeratin-1Keratin-10Models, MolecularMutation, MissenseProtein FoldingProtein Interaction Domains and MotifsProtein MultimerizationProtein Structure, QuaternaryProtein Structure, SecondarySkin DiseasesConceptsFilament assemblyN-terminal hydrophobic pocketIntermediate filament assemblyTetramer assemblyÅ structureÅ resolutionCircular dichroism measurementsTetramer formationAssembly mechanismHydrophobic faceHydrophobic pocketSecondary structureOctamer structureEpidermolytic palmoplantar keratodermaKeratin filamentsIntermediate filamentsMutationsPathogenic mutationsTetramer structureDichroism measurementsAtomic resolutionAssemblyBiochemical determinantsKeratin 1/10TetramerAntimicrobial peptides targeting bacterial ribosome
Lomakin IB, Gagnon MG, Steitz TA. Antimicrobial peptides targeting bacterial ribosome. Oncotarget 2015, 6: 18744-18745. PMID: 26300053, PMCID: PMC4662452, DOI: 10.18632/oncotarget.5114.Peer-Reviewed Original ResearchPosition of eukaryotic initiation factor eIF5B on the 80S ribosome mapped by directed hydroxyl radical probing
Unbehaun A, Marintchev A, Lomakin IB, Didenko T, Wagner G, Hellen C, Pestova TV. Position of eukaryotic initiation factor eIF5B on the 80S ribosome mapped by directed hydroxyl radical probing. The EMBO Journal 2007, 26: 3109-3123. PMID: 17568775, PMCID: PMC1914099, DOI: 10.1038/sj.emboj.7601751.Peer-Reviewed Original ResearchThe Crystal Structure of Yeast Fatty Acid Synthase, a Cellular Machine with Eight Active Sites Working Together
Lomakin IB, Xiong Y, Steitz TA. The Crystal Structure of Yeast Fatty Acid Synthase, a Cellular Machine with Eight Active Sites Working Together. Cell 2007, 129: 319-332. PMID: 17448991, DOI: 10.1016/j.cell.2007.03.013.Peer-Reviewed Original ResearchConceptsCatalytic siteCrystal structureAcyl carrier proteinPantetheine armActive siteCatalytic centerMacromolecular assembliesYeast fatty acid synthaseReaction chamberKetoacyl synthase domainWhole metabolic pathwaysTwo-dimensional diffusionAssemblyCarrier proteinSynthesisStructureComplexesCellular machinesMultiple stepsAcidSitesShellSubstrateInsight into the Tumor Suppression Mechanism from the Structure of Human Polypyrimidine Splicing Factor (PSF/SFPQ) Complexed with a 30mer RNA from Murine Virus-like 30S Transcript‑1
Wang J, Sachpatzidis A, Christian TD, Lomakin IB, Garen A, Konigsberg WH. Insight into the Tumor Suppression Mechanism from the Structure of Human Polypyrimidine Splicing Factor (PSF/SFPQ) Complexed with a 30mer RNA from Murine Virus-like 30S Transcript‑1. Biochemistry 2022, 61: 1723-1734. PMID: 35998361, DOI: 10.1021/acs.biochem.2c00192.Peer-Reviewed Original ResearchConceptsRNA recognition motifSplicing factorsRNA bindingÅ resolution crystal structureTranscript 1DNA-binding domainRNA-binding pocketTumor suppression mechanismNew regulatory mechanismTumor suppressor proteinResolution crystal structureMurine virusesAcid proteinSuppressor proteinRecognition motifLung adenocarcinoma transcript 1Gene expressionRegulatory mechanismsApo structureRNA virusesHuman diseasesRNABinding pocketsHuman metastasesPositive cooperativityRecent insight into intermediate filament structure
Eldirany SA, Lomakin IB, Ho M, Bunick CG. Recent insight into intermediate filament structure. Current Opinion In Cell Biology 2020, 68: 132-143. PMID: 33190098, PMCID: PMC7925366, DOI: 10.1016/j.ceb.2020.10.001.Peer-Reviewed Original ResearchConceptsIntermediate filamentsAssembly mechanismVariable N-terminalMultiple cellular processesCentral rod domainIntermediate filament structureCoil 1BCellular processesStudy of keratinsTail domainFilament assemblyRod domainC-terminalN-terminalElectrostatic surfacePathologic mutationsKey playersFilament structureRecent insightsComplex formationProteinHuman tissuesGlial fibrillary acidic proteinAcidic proteinDomainNonstructural Protein 1 of SARS-CoV-2 Is a Potent Pathogenicity Factor Redirecting Host Protein Synthesis Machinery toward Viral RNA
Yuan S, Peng L, Park JJ, Hu Y, Devarkar SC, Dong MB, Shen Q, Wu S, Chen S, Lomakin IB, Xiong Y. Nonstructural Protein 1 of SARS-CoV-2 Is a Potent Pathogenicity Factor Redirecting Host Protein Synthesis Machinery toward Viral RNA. Molecular Cell 2020, 80: 1055-1066.e6. PMID: 33188728, PMCID: PMC7833686, DOI: 10.1016/j.molcel.2020.10.034.Peer-Reviewed Original ResearchConceptsInternal ribosome entry site RNANonstructural protein 1Host protein synthesis machineryMRNA entry channelProtein synthesis machineryCryo-EM structureProtein 1Major pathogenicity factorsDifferential expression analysisMRNA-seq dataCellular transcriptomePreinitiation complexSynthesis machineryHuman lung originTranslation inhibitionPathogenicity factorsExpression analysisSite RNAHost viabilityNSP1Protein synthesisEntry channelViral proteinsUnknown mechanismViral RNACoronavirus Nsp1: Immune Response Suppression and Protein Expression Inhibition
Yuan S, Balaji S, Lomakin IB, Xiong Y. Coronavirus Nsp1: Immune Response Suppression and Protein Expression Inhibition. Frontiers In Microbiology 2021, 12: 752214. PMID: 34659188, PMCID: PMC8512706, DOI: 10.3389/fmicb.2021.752214.Peer-Reviewed Original ResearchImmune responseImmune response suppressionSARS-CoV-2Nonstructural protein 1Host protein expressionMillions of deathsVaccine developmentProtein expressionProtein 1Causative agentViral RNAExpression inhibitionExpression levelsCOVID-19 pandemicMultiple mechanismsPublic healthViral proteinsGene expression levelsResponse suppressionCoronavirusHost cellsInhibitionCurrent dataGlobal gene expression levelsProtein synthesisPhysical Association of Eukaryotic Initiation Factor 4G (eIF4G) with eIF4A Strongly Enhances Binding of eIF4G to the Internal Ribosomal Entry Site of Encephalomyocarditis Virus and Is Required for Internal Initiation of Translation
Lomakin I, Hellen C, Pestova T. Physical Association of Eukaryotic Initiation Factor 4G (eIF4G) with eIF4A Strongly Enhances Binding of eIF4G to the Internal Ribosomal Entry Site of Encephalomyocarditis Virus and Is Required for Internal Initiation of Translation. Molecular And Cellular Biology 2000, 20: 6019-6029. PMID: 10913184, PMCID: PMC86078, DOI: 10.1128/mcb.20.16.6019-6029.2000.Peer-Reviewed Original ResearchConceptsInternal ribosomal entry siteEMCV internal ribosomal entry siteEIF4GAdditional amino-terminal sequenceEukaryotic initiation factor 4GRNA recognition motifEukaryotic initiation factor 4GIInternal ribosomal entryEntry siteComplex formationBeta-globin mRNAAmino-terminal sequenceEncephalomyocarditis virus internal ribosomal entry siteRibosomal entryRecognition motifLike domainMutational analysisPhysical associationInternal initiationHigh-affinity bindingBinding fragmentSpecific interactionsRNASimilar affinitySpecific high-affinity bindingA Conserved HEAT Domain within eIF4G Directs Assembly of the Translation Initiation Machinery
Marcotrigiano J, Lomakin I, Sonenberg N, Pestova T, Hellen C, Burley S. A Conserved HEAT Domain within eIF4G Directs Assembly of the Translation Initiation Machinery. Molecular Cell 2001, 7: 193-203. PMID: 11172724, DOI: 10.1016/s1097-2765(01)00167-8.Peer-Reviewed Original ResearchConceptsInternal ribosome entry siteTranslation initiation machineryInitiation machineryHEAT domainATP-dependent RNA helicase eIF4AStructure-based site-directed mutagenesisCap-independent translation initiationRNA helicase eIF4ASite-directed mutagenesisPicornaviral internal ribosome-entry siteRibosome entry siteRibosomal complex formationHelicase eIF4ATranslation initiationAlpha-helixEntry siteEIF4AMechanistic insightsX-ray structureComplex formationMachineryBiochemical resultsEssential componentDomainMutagenesisMolecular mechanisms of translation initiation in eukaryotes
Pestova T, Kolupaeva V, Lomakin I, Pilipenko E, Shatsky I, Agol V, Hellen C. Molecular mechanisms of translation initiation in eukaryotes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 7029-7036. PMID: 11416183, PMCID: PMC34618, DOI: 10.1073/pnas.111145798.Peer-Reviewed Original ResearchDendritic BC1 RNA: Functional Role in Regulation of Translation Initiation
Wang H, Iacoangeli A, Popp S, Muslimov IA, Imataka H, Sonenberg N, Lomakin IB, Tiedge H. Dendritic BC1 RNA: Functional Role in Regulation of Translation Initiation. Journal Of Neuroscience 2002, 22: 10232-10241. PMID: 12451124, PMCID: PMC1828542, DOI: 10.1523/jneurosci.22-23-10232.2002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain ChemistryCell-Free SystemCells, CulturedDendritesElectrophoretic Mobility Shift AssayEukaryotic Initiation Factor-4AEukaryotic Initiation FactorsGene Expression RegulationMacromolecular SubstancesNeuronal PlasticityNeuronsPeptide Chain Initiation, TranslationalPoly(A)-Binding ProteinsProtein BiosynthesisRatsRats, Sprague-DawleyRepressor ProteinsRibosomesRNA, MessengerRNA, Small CytoplasmicConceptsLocal protein synthesisBC1 RNATranslation initiationInternal ribosome entry mechanismCap-dependent translation initiationProtein synthesisFunctional roleMessenger RNASmall ribosomal subunitTranslational control mechanismsLevel of initiationDendritic BC1 RNAPlasticity of synapsesRepression pathwaySpecific repressorPreinitiation complexTranslational controlInitiation factorsRibosomal subunitBiochemical experimentsLocal translationInternal initiationRNAEntry mechanismDensity gradient centrifugationPosition of eukaryotic initiation factor eIF1 on the 40S ribosomal subunit determined by directed hydroxyl radical probing
Lomakin IB, Kolupaeva VG, Marintchev A, Wagner G, Pestova TV. Position of eukaryotic initiation factor eIF1 on the 40S ribosomal subunit determined by directed hydroxyl radical probing. Genes & Development 2003, 17: 2786-2797. PMID: 14600024, PMCID: PMC280627, DOI: 10.1101/gad.1141803.Peer-Reviewed Original ResearchAnimalsBinding SitesCodon, InitiatorEukaryotic Initiation Factor-1Eukaryotic Initiation Factor-3HumansHydroxyl RadicalModels, MolecularNucleic Acid ConformationPeptide Chain Initiation, TranslationalProtein BindingProtein FootprintingProtein Structure, TertiaryProtein SubunitsRecombinant Fusion ProteinsRibosomesRNA, MessengerRNA, RibosomalThe fidelity of translation initiation: reciprocal activities of eIF1, IF3 and YciH
Lomakin IB, Shirokikh NE, Yusupov MM, Hellen C, Pestova TV. The fidelity of translation initiation: reciprocal activities of eIF1, IF3 and YciH. The EMBO Journal 2005, 25: 196-210. PMID: 16362046, PMCID: PMC1356347, DOI: 10.1038/sj.emboj.7600904.Peer-Reviewed Original ResearchConceptsInitiator tRNA selectionRibosomal subunitTRNA selectionEukaryotic initiation factors eIF1Common evolutionary originSmall ribosomal subunitInitiation factor eIF1Initiation factor IF3Initiation codon selectionCodon-anticodon mismatchesEIF2-bound GTPRelated conformational changesIF3 functionEvolutionary originSmall ribosomalTranslation initiationInitiation complexInitiation factorsFactor bindingInitiation codonTerminal domainHeterologous systemsCodon selectionInitiator tRNAHeterologous subunitsThe joining of ribosomal subunits in eukaryotes requires eIF5B
Pestova T, Lomakin I, Lee J, Choi S, Dever T, Hellen C. The joining of ribosomal subunits in eukaryotes requires eIF5B. Nature 2000, 403: 332-335. PMID: 10659855, DOI: 10.1038/35002118.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceCatalysisCodon, InitiatorEukaryotic Initiation Factor-1Eukaryotic Initiation Factor-2Eukaryotic Initiation Factor-3Eukaryotic Initiation Factor-5GTP PhosphohydrolasesGuanosine TriphosphateGuanylyl ImidodiphosphateHumansHydrolysisMolecular Sequence DataPeptide Chain Initiation, TranslationalPeptide Initiation FactorsPuromycinRecombinant ProteinsRibosomesRNA, MessengerConceptsEIF2-bound GTPEukaryotic initiation factor 3RNA ternary complexRibosome-dependent GTPase activityInitiation factor IF2Initiation factor 3Eukaryotic protein synthesisRibosomal subunitInitiation codonGTPase activityProtein synthesisMessenger RNASubunitsTernary complexFactor 3GTPComplexesEukaryotesEIF5EIF5BEIF2EIF4BEIF1ARibosomesIF2The initiation of mammalian protein synthesis and mRNA scanning mechanism
Lomakin IB, Steitz TA. The initiation of mammalian protein synthesis and mRNA scanning mechanism. Nature 2013, 500: 307-311. PMID: 23873042, PMCID: PMC3748252, DOI: 10.1038/nature12355.Peer-Reviewed Original ResearchConceptsSmall ribosomal subunitTranslation initiationRibosomal subunitMammalian translation initiationProtein synthesisInitiator transfer RNAMammalian protein synthesisMultiple initiation factorsMRNA scanningTransfer RNAInitiation factorsInitiation codonConformational changesMessenger RNAFunctional implicationsEukaryotesDistinct stepsP siteSubunitsRNAFunctional stateEIF1ARibosomesEIF1CodonCrystal structure of the DENR-MCT-1 complex revealed zinc-binding site essential for heterodimer formation
Lomakin IB, Dmitriev SE, Steitz TA. Crystal structure of the DENR-MCT-1 complex revealed zinc-binding site essential for heterodimer formation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 116: 528-533. PMID: 30584092, PMCID: PMC6329987, DOI: 10.1073/pnas.1809688116.Peer-Reviewed Original ResearchConceptsTranslation initiationHeterodimer formationUnconventional translation initiationNoncanonical translation initiationZinc-binding siteMechanism of regulationUpstream reading framesIon-binding sitesRibosome recyclingReading frameTerminal domainTranslation reinitiationCysteine residuesAtomic detailHeterodimersMCT-1Crystal structureSpecific setReinitiationRibosomesProteinCysteineMRNAResiduesSitesSarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome
Batool Z, Lomakin IB, Polikanov YS, Bunick CG. Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 20530-20537. PMID: 32817463, PMCID: PMC7456112, DOI: 10.1073/pnas.2008671117.Peer-Reviewed Original ResearchThe mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin
Roy RN, Lomakin IB, Gagnon MG, Steitz TA. The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin. Nature Structural & Molecular Biology 2015, 22: 466-469. PMID: 25984972, PMCID: PMC4456192, DOI: 10.1038/nsmb.3031.Peer-Reviewed Original Research