Kokic, Goran

[["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","1104"],["dc.bibliographiccitation.issue","6264"],["dc.bibliographiccitation.journal","Science"],["dc.bibliographiccitation.lastpage","1107"],["dc.bibliographiccitation.volume","350"],["dc.contributor.author","Holtkamp, Wolf"],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Jäger, Marcus"],["dc.contributor.author","Mittelstaet, Joerg"],["dc.contributor.author","Komar, Anton A."],["dc.contributor.author","Rodnina, Marina V."],["dc.date.accessioned","2017-09-07T11:54:52Z"],["dc.date.available","2017-09-07T11:54:52Z"],["dc.date.issued","2015"],["dc.description.abstract","Protein domains can fold into stable tertiary structures while they are synthesized on the ribosome. We used a high-performance, reconstituted in vitro translation system to investigate the folding of a small five-helix protein domain-the N-terminal domain of Escherichia coli N5-glutamine methyltransferase HemK-in real time. Our observations show that cotranslational folding of the protein, which folds autonomously and rapidly in solution, proceeds through a compact, non-native conformation that forms within the peptide tunnel of the ribosome. The compact state rearranges into a native-like structure immediately after the full domain sequence has emerged from the ribosome. Both folding transitions are rate-limited by translation, allowing for quasi-equilibrium sampling of the conformational space restricted by the ribosome. Cotranslational folding may be typical of small, intrinsically rapidly folding protein domains."],["dc.identifier.doi","10.1126/science.aad0344"],["dc.identifier.gro","3141785"],["dc.identifier.isi","000366422600047"],["dc.identifier.pmid","26612953"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1046"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1095-9203"],["dc.relation.issn","0036-8075"],["dc.title","Cotranslational protein folding on the ribosome monitored in real time"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Nature"],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Wagner, Felix R."],["dc.contributor.author","Chernev, Aleksandar"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2021-10-01T09:57:44Z"],["dc.date.available","2021-10-01T09:57:44Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract Transcription-coupled DNA repair removes bulky DNA lesions from the genome 1,2 and protects cells against ultraviolet (UV) irradiation 3 . Transcription-coupled DNA repair begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4 CSA and UV-stimulated scaffold protein A (UVSSA) 3 . Here we provide five high-resolution structures of Pol II transcription complexes containing human transcription-coupled DNA repair factors and the elongation factors PAF1 complex (PAF) and SPT6. Together with biochemical and published 3,4 data, the structures provide a model for transcription–repair coupling. Stalling of Pol II at a DNA lesion triggers replacement of the elongation factor DSIF by CSB, which binds to PAF and moves upstream DNA to SPT6. The resulting elongation complex, EC TCR , uses the CSA-stimulated translocase activity of CSB to pull on upstream DNA and push Pol II forward. If the lesion cannot be bypassed, CRL4 CSA spans over the Pol II clamp and ubiquitylates the RPB1 residue K1268, enabling recruitment of TFIIH to UVSSA and DNA repair. Conformational changes in CRL4 CSA lead to ubiquitylation of CSB and to release of transcription-coupled DNA repair factors before transcription may continue over repaired DNA."],["dc.identifier.doi","10.1038/s41586-021-03906-4"],["dc.identifier.pii","3906"],["dc.identifier.pmid","34526721"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/89904"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/340"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1476-4687"],["dc.relation.issn","0028-0836"],["dc.relation.workinggroup","RG Cramer"],["dc.rights","CC BY 4.0"],["dc.title","Structural basis of human transcription–DNA repair coupling"],["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","833"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Nature Structural & Molecular Biology"],["dc.bibliographiccitation.lastpage","840"],["dc.bibliographiccitation.volume","25"],["dc.contributor.author","Boehning, Marc"],["dc.contributor.author","Dugast-Darzacq, Claire"],["dc.contributor.author","Rankovic, Marija"],["dc.contributor.author","Hansen, Anders S."],["dc.contributor.author","Yu, Taekyung"],["dc.contributor.author","Marie-Nelly, Herve"],["dc.contributor.author","McSwiggen, David T."],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Dailey, Gina M."],["dc.contributor.author","Cramer, Patrick"],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2022-03-01T11:46:02Z"],["dc.date.available","2022-03-01T11:46:02Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1038/s41594-018-0112-y"],["dc.identifier.pii","112"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103536"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.eissn","1545-9985"],["dc.relation.issn","1545-9993"],["dc.rights.uri","http://www.springer.com/tdm"],["dc.title","RNA polymerase II clustering through carboxy-terminal domain phase separation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["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"]]