Nicole Bertoletti, PhD
Cards
About
Research
Publications
Featured Publications
Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine
Bertoletti N, Chan AH, Schinazi RF, Yin YW, Anderson KS. Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine. Protein Science 2019, 28: 1664-1675. PMID: 31301259, PMCID: PMC6699100, DOI: 10.1002/pro.3681.Peer-Reviewed Original ResearchConceptsHIV-1Severe drug toxicityActive antiretroviral therapySuccessful treatment regimenMajor health issueActive triphosphate formHIV-1 drugsReverse transcriptaseHIV-1 reverse transcriptaseAntiretroviral therapyOff-target side effectsTreatment regimenRetroviruses HIV-1Drug toxicityReverse transcriptase enzymeSide effectsRT inhibitorsNew infectionsViral replicationHealth issuesTarget toxicityTriphosphate formNext-generation therapeuticsNRTIsTranscriptase enzymeCryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention
Krimmer S, Bertoletti N, Suzuki Y, Katic L, Mohanty J, Shu S, Lee S, Lax I, Mi W, Schlessinger J. Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2300054120. PMID: 36943885, PMCID: PMC10068818, DOI: 10.1073/pnas.2300054120.Peer-Reviewed Original ResearchConceptsOncogenic KIT mutantsStem cell factorKIT mutantsHomotypic contactsCryo-EM analysisUnexpected structural plasticityLigand stem cell factorElectron microscopy structural analysisReceptor tyrosine kinase KITOncogenic mutantsHematopoietic stem cellsKIT dimerizationTyrosine kinase KITD5 regionPlasma membraneMutational analysisMutantsExtracellular domainGerm cellsHuman cancersSomatic gainCell factorStructural plasticityStem cellsKinase KITNew Insights into Human 17β-Hydroxysteroid Dehydrogenase Type 14: First Crystal Structures in Complex with a Steroidal Ligand and with a Potent Nonsteroidal Inhibitor
Bertoletti N, Braun F, Lepage M, Möller G, Adamski J, Heine A, Klebe G, Marchais-Oberwinkler S. New Insights into Human 17β-Hydroxysteroid Dehydrogenase Type 14: First Crystal Structures in Complex with a Steroidal Ligand and with a Potent Nonsteroidal Inhibitor. Journal Of Medicinal Chemistry 2016, 59: 6961-6967. PMID: 27362750, DOI: 10.1021/acs.jmedchem.6b00293.Peer-Reviewed Original ResearchConceptsCrystal structureStructure-based inhibitor designFirst crystal structureNonsteroidal inhibitorsPotent nonsteroidal inhibitorSDR enzymesInhibitor designHolo formHuman enzymeNatural variantsSteroidal ligandsTernary complexNew insightsComplexesSimilar structureEnzymeStructureType 14InhibitorsLigandsVariants
2022
Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
Frey KM, Bertoletti N, Chan AH, Ippolito JA, Bollini M, Spasov KA, Jorgensen WL, Anderson KS. Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase. Frontiers In Molecular Biosciences 2022, 9: 805187. PMID: 35237658, PMCID: PMC8882919, DOI: 10.3389/fmolb.2022.805187.Peer-Reviewed Original ResearchCrystal structureStructure-based drug designKey interactionsNon-nucleoside inhibitorsMolecular dynamics simulationsStructure-activity relationshipsCompound classesAttractive drug targetDrug designActivity relationshipsAdditional complexesDynamics simulationsStructural studiesNon-nucleoside binding sitePocket of RTComplexesNon-nucleoside reverse transcriptase inhibitor nevirapineRT crystal structuresStructureDrug targetsBinding sitesAntiviral dataHIV-1 reverse transcriptaseCompoundsReverse transcriptase inhibitor nevirapine
2021
Covalent Inhibition of Wild-Type HIV‑1 Reverse Transcriptase Using a Fluorosulfate Warhead
Ippolito JA, Niu H, Bertoletti N, Carter ZJ, Jin S, Spasov KA, Cisneros J, Valhondo M, Cutrona KJ, Anderson KS, Jorgensen WL. Covalent Inhibition of Wild-Type HIV‑1 Reverse Transcriptase Using a Fluorosulfate Warhead. ACS Medicinal Chemistry Letters 2021, 12: 249-255. PMID: 33603971, PMCID: PMC7883463, DOI: 10.1021/acsmedchemlett.0c00612.Peer-Reviewed Original Research
2020
Post-Catalytic Complexes with Emtricitabine or Stavudine and HIV-1 Reverse Transcriptase Reveal New Mechanistic Insights for Nucleotide Incorporation and Drug Resistance
Bertoletti N, Chan AH, Schinazi RF, Anderson KS. Post-Catalytic Complexes with Emtricitabine or Stavudine and HIV-1 Reverse Transcriptase Reveal New Mechanistic Insights for Nucleotide Incorporation and Drug Resistance. Molecules 2020, 25: 4868. PMID: 33096918, PMCID: PMC7587939, DOI: 10.3390/molecules25204868.Peer-Reviewed Original ResearchStructure-Guided Identification of DNMT3B Inhibitors
Newton AS, Faver JC, Micevic G, Muthusamy V, Kudalkar SN, Bertoletti N, Anderson KS, Bosenberg MW, Jorgensen WL. Structure-Guided Identification of DNMT3B Inhibitors. ACS Medicinal Chemistry Letters 2020, 11: 971-976. PMID: 32435413, PMCID: PMC7236258, DOI: 10.1021/acsmedchemlett.0c00011.Peer-Reviewed Original ResearchUltrahigh-performance liquid chromatographyStructure-activity dataGood selectivityExploratory synthesisStructure-Guided IdentificationCrystal structureVirtual screeningAnalytical assaysActive compoundsLiquid chromatographyCompoundsSmall molecule inhibitorsPotent beingHomology modelAdditional inhibitorsAnaloguesFluorogenic assayMolecule inhibitorsSelectivitySynthesisChromatographyDockingStructureHereinIC
2019
Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV
Kudalkar SN, Ullah I, Bertoletti N, Mandl HK, Cisneros JA, Beloor J, Chan AH, Quijano E, Saltzman WM, Jorgensen WL, Kumar P, Anderson KS. Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV. Antiviral Research 2019, 167: 110-116. PMID: 31034849, PMCID: PMC6554724, DOI: 10.1016/j.antiviral.2019.04.010.Peer-Reviewed Original ResearchConceptsCombination antiretroviral therapyBALB/c miceHIV-1C miceT cellsHuman immunodeficiency virus type 1 (HIV-1) infectionImmune deficiency syndrome (AIDS) patientsAntiviral activityNon-nucleoside reverse transcriptase inhibitorNovel non-nucleoside reverse transcriptase inhibitorVirus type 1 infectionDrug-resistant HIV-1Observed serum concentrationsHIV-1 infectionType 1 infectionReverse transcriptase inhibitorNon-nucleoside reversePotent antiviral activityHIV therapeutic agentsSignificant antiviral activitySerum residence timeHIV-1 NNRTIsAntiretroviral therapyClinical benefitSerum concentrationsMutational and structural studies uncover crucial amino acids determining activity and stability of 17β-HSD14
Badran M, Bertoletti N, Keils A, Heine A, Klebe G, Marchais-Oberwinkler S. Mutational and structural studies uncover crucial amino acids determining activity and stability of 17β-HSD14. The Journal Of Steroid Biochemistry And Molecular Biology 2019, 189: 135-144. PMID: 30836176, DOI: 10.1016/j.jsbmb.2019.02.009.Peer-Reviewed Original ResearchConceptsAmino acidsAdjacent monomersSite-directed mutagenesisCrucial amino acidsIndividual amino acidsEnzymatic functionCatalytic triadEnzyme variantsActive siteTerminal loopPresence of NADDisulfide bridgesNeighboring monomerCatalytic centerX-ray crystallographyDimer formationEnzyme kineticsStructural studiesTyr253His93Gln148EnzymeLatter interactionCys255Type 14
2018
DRONE: Direct Tracking of DNA Cytidine Deamination and Other DNA Modifying Activities
Sasaki T, Kudalkar SN, Bertoletti N, Anderson KS. DRONE: Direct Tracking of DNA Cytidine Deamination and Other DNA Modifying Activities. Analytical Chemistry 2018, 90: 11735-11740. PMID: 30256094, PMCID: PMC6410358, DOI: 10.1021/acs.analchem.8b01405.Peer-Reviewed Original ResearchConceptsDNA modificationsCytidine deaminationDNA cytidine deaminationNovel DNA modificationUltra-high performance liquid chromatographyDNA-modifying enzymesImportant DNA modificationImportant biological rolesCytosine methylationHigh-performance liquid chromatographyPerformance liquid chromatographyBiological roleAntiviral defenseCatalytic polypeptideVersatile detectionOligonucleotide substratesDeamination eventsLiquid chromatographyDirect resolutionUracil conversionAnalytical methodEnzymeDeaminationEnzyme inhibitionDNA modifying activity