Hillen, Hauke S.

[["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.firstpage","1525"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Cell"],["dc.bibliographiccitation.lastpage","1536"],["dc.bibliographiccitation.volume","179"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Bartuli, Julia"],["dc.contributor.author","Grimm, Clemens"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Bedenk, Kristina"],["dc.contributor.author","Szalay, Aladar A"],["dc.contributor.author","Fischer, Utz"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2020-04-02T14:06:45Z"],["dc.date.available","2020-04-02T14:06:45Z"],["dc.date.issued","2019-12-12"],["dc.description.abstract","Poxviruses use virus-encoded multisubunit RNA polymerases (vRNAPs) and RNA-processing factors to generate m7G-capped mRNAs in the host cytoplasm. In the accompanying paper, we report structures of core and complete vRNAP complexes of the prototypic Vaccinia poxvirus (Grimm et al., 2019; in this issue of Cell). Here, we present the cryo-electron microscopy (cryo-EM) structures of Vaccinia vRNAP in the form of a transcribing elongation complex and in the form of a co-transcriptional capping complex that contains the viral capping enzyme (CE). The trifunctional CE forms two mobile modules that bind the polymerase surface around the RNA exit tunnel. RNA extends from the vRNAP active site through this tunnel and into the active site of the CE triphosphatase. Structural comparisons suggest that growing RNA triggers large-scale rearrangements on the surface of the transcription machinery during the transition from transcription initiation to RNA capping and elongation. Our structures unravel the basis for synthesis and co-transcriptional modification of poxvirus RNA."],["dc.identifier.doi","10.1016/j.cell.2019.11.023"],["dc.identifier.pmid","31835031"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/63541"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/32"],["dc.language.iso","en"],["dc.notes","Research funded by Deutsche Forschungsgemeinschaft | Volkswagen Foundation | Excellence Strategy (EXC 2067/1- 390729940) | European Research Council Advanced Investigator Grant TRANSREGULON (693023)"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1097-4172"],["dc.relation.issn","0092-8674"],["dc.relation.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.title","Structural Basis of Poxvirus Transcription: Transcribing and Capping Vaccinia Complexes"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","154-156"],["dc.bibliographiccitation.issue","7819"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.lastpage","156"],["dc.bibliographiccitation.volume","584"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Farnung, Lucas"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Tegunov, Dimitry"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2022-02-21T13:20:58Z"],["dc.date.available","2022-02-21T13:20:58Z"],["dc.date.issued","2020"],["dc.description.abstract","The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes1-3. Here we present a cryo-electron microscopy structure of the SARS-CoV-2 RdRp in an active form that mimics the replicating enzyme. The structure comprises the viral proteins non-structural protein 12 (nsp12), nsp8 and nsp7, and more than two turns of RNA template-product duplex. The active-site cleft of nsp12 binds to the first turn of RNA and mediates RdRp activity with conserved residues. Two copies of nsp8 bind to opposite sides of the cleft and position the second turn of RNA. Long helical extensions in nsp8 protrude along exiting RNA, forming positively charged 'sliding poles'. These sliding poles can account for the known processivity of RdRp that is required for replicating the long genome of coronaviruses3. Our results enable a detailed analysis of the inhibitory mechanisms that underlie the antiviral activity of substances such as remdesivir, a drug for the treatment of coronavirus disease 2019 (COVID-19)4."],["dc.identifier.doi","10.1038/s41586-020-2368-8"],["dc.identifier.pmid","32438371"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/100148"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/44"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/22"],["dc.language.iso","en"],["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","1476-4687"],["dc.relation.issn","0028-0836"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.relation.workinggroup","RG Cramer"],["dc.title","Structure of replicating SARS-CoV-2 polymerase"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.contributor.author","Kabinger, Florian"],["dc.contributor.author","Stiller, Carina"],["dc.contributor.author","Schmitzová, Jana"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Höbartner, Claudia"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2022-02-23T16:35:37Z"],["dc.date.available","2022-02-23T16:35:37Z"],["dc.date.issued","2021"],["dc.identifier.doi","10.1101/2021.05.11.443555"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/100378"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/258"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/145"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/12"],["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.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.title","Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis"],["dc.type","preprint"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.contributor.author","Jochheim, Florian A."],["dc.contributor.author","Tegunov, Dimitry"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Schmitzova, Jana"],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2022-02-23T16:35:50Z"],["dc.date.available","2022-02-23T16:35:50Z"],["dc.date.issued","2021"],["dc.identifier.doi","10.1101/2021.03.23.436644"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/100381"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/291"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/147"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/11"],["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.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.title","Dimeric form of SARS-CoV-2 polymerase"],["dc.type","preprint"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1537"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Cell"],["dc.bibliographiccitation.lastpage","1550"],["dc.bibliographiccitation.volume","179"],["dc.contributor.author","Grimm, Clemens"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Bedenk, Kristina"],["dc.contributor.author","Bartuli, Julia"],["dc.contributor.author","Neyer, Simon"],["dc.contributor.author","Zhang, Qian"],["dc.contributor.author","Hüttenhofer, Alexander"],["dc.contributor.author","Erlacher, Matthias"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Schlosser, Andreas"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Böttcher, Bettina"],["dc.contributor.author","Szalay, Aladar A"],["dc.contributor.author","Cramer, Patrick"],["dc.contributor.author","Fischer, Utz"],["dc.date.accessioned","2020-04-02T14:08:48Z"],["dc.date.available","2020-04-02T14:08:48Z"],["dc.date.issued","2019-12-12"],["dc.description.abstract","Poxviruses encode a multisubunit DNA-dependent RNA polymerase (vRNAP) that carries out viral gene expression in the host cytoplasm. We report cryo-EM structures of core and complete vRNAP enzymes from Vaccinia virus at 2.8 Å resolution. The vRNAP core enzyme resembles eukaryotic RNA polymerase II (Pol II) but also reveals many virus-specific features, including the transcription factor Rap94. The complete enzyme additionally contains the transcription factor VETF, the mRNA processing factors VTF/CE and NPH-I, the viral core protein E11, and host tRNAGln. This complex can carry out the entire early transcription cycle. The structures show that Rap94 partially resembles the Pol II initiation factor TFIIB, that the vRNAP subunit Rpo30 resembles the Pol II elongation factor TFIIS, and that NPH-I resembles chromatin remodeling enzymes. Together with the accompanying paper (Hillen et al., 2019), these results provide the basis for unraveling the mechanisms of poxvirus transcription and RNA processing."],["dc.identifier.doi","10.1016/j.cell.2019.11.024"],["dc.identifier.pmid","31835032"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/63542"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/34"],["dc.language.iso","en"],["dc.notes","Research funded by Deutsche Forschungsgemeinschaft (SPP193518-1SFB860Fi 573 7-2) | European Research Council (693023) | Volkswagen Foundation | Austrian Science Fund (P-30486-BBLSFB F4411) | Germany’s Excellence Strategy (EXC 2067/1- 390729940) | Genelux Corporation"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1097-4172"],["dc.relation.issn","0092-8674"],["dc.relation.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.title","Structural Basis of Poxvirus Transcription: Vaccinia RNA Polymerase Complexes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["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"]]