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
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 Research
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 activityStructure-based design and profiling of novel 17β-HSD14 inhibitors
Braun F, Bertoletti N, Möller G, Adamski J, Frotscher M, Guragossian N, Gírio P, Le Borgne M, Ettouati L, Falson P, Müller S, Vollmer G, Heine A, Klebe G, Marchais-Oberwinkler S. Structure-based design and profiling of novel 17β-HSD14 inhibitors. European Journal Of Medicinal Chemistry 2018, 155: 61-76. PMID: 29859505, DOI: 10.1016/j.ejmech.2018.05.029.Peer-Reviewed Original ResearchConceptsCrystal structureChemical probesStructure-based optimizationStructure-based designInhibitor-enzyme complexGood selectivity profilePromising chemical probeGood solubilityCompound 1Hydroxyl groupsSubstitution patternPhysiological roleSelectivity profileTarget enzymeNonsteroidal inhibitorsPosition 17EnzymeEstrogen receptor alphaReceptor alphaCompoundsPotent inhibitorInhibitory activityProfilingInhibitorsHighest inhibition
2016
First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme
Braun F, Bertoletti N, Möller G, Adamski J, Steinmetzer T, Salah M, Abdelsamie A, van Koppen C, Heine A, Klebe G, Marchais-Oberwinkler S. First Structure–Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme. Journal Of Medicinal Chemistry 2016, 59: 10719-10737. PMID: 27933965, DOI: 10.1021/acs.jmedchem.6b01436.Peer-Reviewed Original ResearchConceptsStructure-activity relationshipsExtended H-bonding networkH-bonding networkFirst structure-activity relationshipsLigand-based approachesEnzyme active siteCrystallographic structure analysisNonsteroidal inhibitorsScaffold diversityChemical modificationHydroxyl groupsActive siteCrystal structureInteresting hitsPotent compoundsStrong affinityStructure analysisBest inhibitorCompoundsInhibitory activitySDR familyStabilization processHigh affinityAffinitySelectivity