Dienemann, Christian

[["dc.bibliographiccitation.journal","Nature Structural & Molecular Biology"],["dc.contributor.author","Kabinger, Florian"],["dc.contributor.author","Stiller, Carina"],["dc.contributor.author","Schmitzová, Jana"],["dc.contributor.author","Dienemann, C."],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Höbartner, Claudia"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2021-09-01T06:42:22Z"],["dc.date.available","2021-09-01T06:42:22Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, β- d - N 4 -hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp–RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir."],["dc.identifier.doi","10.1038/s41594-021-00651-0"],["dc.identifier.pii","651"],["dc.identifier.pmid","34381216"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/89038"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/381"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/171"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/28"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-455"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.eissn","1545-9985"],["dc.relation.issn","1545-9993"],["dc.relation.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY 4.0"],["dc.title","Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","493"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Nature Structural & Molecular Biology"],["dc.bibliographiccitation.lastpage","501"],["dc.bibliographiccitation.volume","29"],["dc.contributor.author","Dombrowski, Marco"],["dc.contributor.author","Engeholm, Maik"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Dodonova, Svetlana"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2022-06-01T09:39:10Z"],["dc.date.available","2022-06-01T09:39:10Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract Throughout the genome, nucleosomes often form regular arrays that differ in nucleosome repeat length (NRL), occupancy of linker histone H1 and transcriptional activity. Here, we report cryo-EM structures of human H1-containing tetranucleosome arrays with four physiologically relevant NRLs. The structures show a zig-zag arrangement of nucleosomes, with nucleosomes 1 and 3 forming a stack. H1 binding to stacked nucleosomes depends on the NRL, whereas H1 always binds to the non-stacked nucleosomes 2 and 4. Short NRLs lead to altered trajectories of linker DNA, and these altered trajectories sterically impair H1 binding to the stacked nucleosomes in our structures. As the NRL increases, linker DNA trajectories relax, enabling H1 contacts and binding. Our results provide an explanation for why arrays with short NRLs are depleted of H1 and suited for transcription, whereas arrays with long NRLs show full H1 occupancy and can form transcriptionally silent heterochromatin regions."],["dc.identifier.doi","10.1038/s41594-022-00768-w"],["dc.identifier.pii","768"],["dc.identifier.pmid","35581345"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/108404"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/531"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-572"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1545-9985"],["dc.relation.issn","1545-9993"],["dc.relation.workinggroup","RG Cramer"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Histone H1 binding to nucleosome arrays depends on linker DNA length and trajectory"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","713"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Nature Structural & Molecular Biology"],["dc.bibliographiccitation.lastpage","723"],["dc.bibliographiccitation.volume","28"],["dc.contributor.author","Bhatta, Arjun"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Cramer, Patrick"],["dc.contributor.author","Hillen, Hauke S."],["dc.date.accessioned","2021-10-01T09:57:57Z"],["dc.date.available","2021-10-01T09:57:57Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract Human mitochondrial transcripts contain messenger and ribosomal RNAs flanked by transfer RNAs (tRNAs), which are excised by mitochondrial RNase (mtRNase) P and Z to liberate all RNA species. In contrast to nuclear or bacterial RNase P, mtRNase P is not a ribozyme but comprises three protein subunits that carry out RNA cleavage and methylation by unknown mechanisms. Here, we present the cryo-EM structure of human mtRNase P bound to precursor tRNA, which reveals a unique mechanism of substrate recognition and processing. Subunits TRMT10C and SDR5C1 form a subcomplex that binds conserved mitochondrial tRNA elements, including the anticodon loop, and positions the tRNA for methylation. The endonuclease PRORP is recruited and activated through interactions with its PPR and nuclease domains to ensure precise pre-tRNA cleavage. The structure provides the molecular basis for the first step of RNA processing in human mitochondria."],["dc.identifier.doi","10.1038/s41594-021-00637-y"],["dc.identifier.pii","637"],["dc.identifier.pmid","34489609"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/89952"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/337"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/154"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/9"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.eissn","1545-9985"],["dc.relation.issn","1545-9993"],["dc.relation.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY 4.0"],["dc.title","Structural basis of RNA processing by human mitochondrial RNase P"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","279"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Tegunov, Dimitry"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Seitz, Florian"],["dc.contributor.author","Schmitzova, Jana"],["dc.contributor.author","Farnung, Lucas"],["dc.contributor.author","Siewert, Aaron"],["dc.contributor.author","Höbartner, Claudia"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2021-08-12T07:44:55Z"],["dc.date.available","2021-08-12T07:44:55Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication."],["dc.identifier.doi","10.1038/s41467-020-20542-0"],["dc.identifier.pii","20542"],["dc.identifier.pmid","33436624"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88330"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/113"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/17"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-448"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.eissn","2041-1723"],["dc.relation.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY 4.0"],["dc.title","Mechanism of SARS-CoV-2 polymerase stalling by remdesivir"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","19"],["dc.bibliographiccitation.journal","The EMBO Journal"],["dc.bibliographiccitation.volume","40"],["dc.contributor.affiliation","Güttler, Thomas; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Aksu, Metin; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Dickmanns, Antje; 2Institute of Molecular Oncology GZMB University Medical Center Göttingen Germany"],["dc.contributor.affiliation","Stegmann, Kim M.; 2Institute of Molecular Oncology GZMB University Medical Center Göttingen Germany"],["dc.contributor.affiliation","Gregor, Kathrin; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Rees, Renate; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Taxer, Waltraud; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Rymarenko, Oleh; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Schünemann, Jürgen; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Dienemann, Christian; 3Department of Molecular Biology Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Gunkel, Philip; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Mussil, Bianka; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Krull, Jens; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Teichmann, Ulrike; 4Animal facility Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.affiliation","Groß, Uwe; 5Institute of Medical Microbiology and Virology University Medical Center Göttingen Germany"],["dc.contributor.affiliation","Cordes, Volker C; 1Department of Cellular Logistics Max Planck Institute for Biophysical Chemistry Göttingen Germany"],["dc.contributor.author","Güttler, Thomas"],["dc.contributor.author","Aksu, Metin"],["dc.contributor.author","Dickmanns, Antje"],["dc.contributor.author","Stegmann, Kim M."],["dc.contributor.author","Gregor, Kathrin"],["dc.contributor.author","Rees, Renate"],["dc.contributor.author","Taxer, Waltraud"],["dc.contributor.author","Rymarenko, Oleh"],["dc.contributor.author","Schünemann, Jürgen"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Görlich, Dirk"],["dc.contributor.author","Groß, Uwe"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2021-09-01T06:38:23Z"],["dc.date.available","2021-09-01T06:38:23Z"],["dc.date.issued","2021"],["dc.date.updated","2022-03-21T10:12:03Z"],["dc.description.abstract","Abstract Monoclonal anti‐SARS‐CoV‐2 immunoglobulins represent a treatment option for COVID‐19. However, their production in mammalian cells is not scalable to meet the global demand. Single‐domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. Using alpaca immune libraries against the receptor‐binding domain (RBD) of the SARS‐CoV‐2 Spike protein, we isolated 45 infection‐blocking VHH antibodies. These include nanobodies that can withstand 95°C. The most effective VHH antibody neutralizes SARS‐CoV‐2 at 17–50 pM concentration (0.2–0.7 µg per liter), binds the open and closed states of the Spike, and shows a tight RBD interaction in the X‐ray and cryo‐EM structures. The best VHH trimers neutralize even at 40 ng per liter. We constructed nanobody tandems and identified nanobody monomers that tolerate the K417N/T, E484K, N501Y, and L452R immune‐escape mutations found in the Alpha, Beta, Gamma, Epsilon, Iota, and Delta/Kappa lineages. We also demonstrate neutralization of the Beta strain at low‐picomolar VHH concentrations. We further discovered VHH antibodies that enforce native folding of the RBD in the E. coli cytosol, where its folding normally fails. Such “fold‐promoting” nanobodies may allow for simplified production of vaccines and their adaptation to viral escape‐mutations."],["dc.description.abstract","SYNOPSIS image Effective treatment options for SARS‐CoV‐2 infections/COVID‐19 are still sparse. This study revealed highly potent therapeutic nanobodies/single‐domain (VHH) antibodies that neutralize SARS‐CoV‐2 and its emerging immune‐escape mutants. Alpaca immune libraries yielded 45 VHHs (of 22 sequence classes) that target two epitopes of the SARS‐CoV‐2 receptor‐binding domain (RBD) and block infection. The lead nanobody monomers are hyperthermostable, bind the RBD with low‐picomolar affinity and neutralize the virus at a concentration of 0.2–0.7 micrograms per liter (IC99+). Enhancement of the nanobodies' avidity by trimerization with the collagen XVIII NC1 domain yields neutralizers that block SARS‐CoV‐2 at concentrations as low as 40 nanograms per liter (IC99+). Clinical candidates include nanobody trimers, tandem fusions and monomers that bind the major SARS‐CoV‐2 immune‐escape mutants with high affinity and neutralize, e.g., the Beta/B.1.351 variant. “Fold‐promoting” nanobodies assist de novo protein folding in the E. coli cytosol, as demonstrated with nanobody⋅RBD complexes."],["dc.description.abstract","Single‐domain camelid antibodies that neutralize a range of common and emerging immune‐escape mutant strains of SARS‐CoV‐2 may constitute an easily‐producible option for treatment of COVID‐19 patients. image"],["dc.description.sponsorship","Max Planck Society http://dx.doi.org/10.13039/501100004189"],["dc.description.sponsorship","Max Planck Foundation"],["dc.identifier.doi","10.15252/embj.2021107985"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88920"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-455"],["dc.relation.eissn","1460-2075"],["dc.relation.issn","0261-4189"],["dc.rights","This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited."],["dc.title","Neutralization of SARS‐CoV‐2 by highly potent, hyperthermostable, and mutation‐tolerant nanobodies"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","2885"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Chernev, Aleksandar"],["dc.contributor.author","Tegunov, Dimitry"],["dc.contributor.author","Dienemann, C."],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2019-07-22T12:01:28Z"],["dc.date.available","2019-07-22T12:01:28Z"],["dc.date.issued","2019"],["dc.description.abstract","Nucleotide excision repair (NER) is the major DNA repair pathway that removes UV-induced and bulky DNA lesions. There is currently no structure of NER intermediates, which form around the large multisubunit transcription factor IIH (TFIIH). Here we report the cryo-EM structure of an NER intermediate containing TFIIH and the NER factor XPA. Compared to its transcription conformation, the TFIIH structure is rearranged such that its ATPase subunits XPB and XPD bind double- and single-stranded DNA, consistent with their translocase and helicase activities, respectively. XPA releases the inhibitory kinase module of TFIIH, displaces a 'plug' element from the DNA-binding pore in XPD, and together with the NER factor XPG stimulates XPD activity. Our results explain how TFIIH is switched from a transcription to a repair factor, and provide the basis for a mechanistic analysis of the NER pathway."],["dc.identifier.doi","10.1038/s41467-019-10745-5"],["dc.identifier.pmid","31253769"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16290"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/61789"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2041-1723"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Structural basis of TFIIH activation for nucleotide excision repair"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","999"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Communications Biology"],["dc.bibliographiccitation.volume","4"],["dc.contributor.author","Jochheim, Florian A."],["dc.contributor.author","Tegunov, Dimitry"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Schmitzová, Jana"],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2021-10-01T09:57:46Z"],["dc.date.available","2021-10-01T09:57:46Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract The coronavirus SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) to replicate and transcribe its genome. Previous structures of the RdRp revealed a monomeric enzyme composed of the catalytic subunit nsp12, two copies of subunit nsp8, and one copy of subunit nsp7. Here we report an alternative, dimeric form of the enzyme and resolve its structure at 5.5 Å resolution. In this structure, the two RdRps contain only one copy of nsp8 each and dimerize via their nsp7 subunits to adopt an antiparallel arrangement. We speculate that the RdRp dimer facilitates template switching during production of sub-genomic RNAs."],["dc.identifier.doi","10.1038/s42003-021-02529-9"],["dc.identifier.pii","2529"],["dc.identifier.pmid","34429502"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/89909"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/334"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/153"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/10"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.eissn","2399-3642"],["dc.relation.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY 4.0"],["dc.title","The structure of a dimeric form of SARS-CoV-2 polymerase"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]