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  1. Article ; Online: Halting coronavirus polymerase.

    Kirchdoerfer, Robert N

    The Journal of biological chemistry

    2020  Volume 295, Issue 15, Page(s) 4780–4781

    Abstract: The nucleotide analogue remdesivir is an investigational drug for the treatment of human coronavirus infection. Remdesivir is a phosphoramidate prodrug and is known to target viral RNA-dependent RNA polymerases. In this issue, ... ...

    Abstract The nucleotide analogue remdesivir is an investigational drug for the treatment of human coronavirus infection. Remdesivir is a phosphoramidate prodrug and is known to target viral RNA-dependent RNA polymerases. In this issue, Gordon
    MeSH term(s) Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Animals ; Antiviral Agents/pharmacology ; Coronavirus/drug effects ; Coronavirus/enzymology ; Coronavirus/physiology ; Coronavirus Infections/drug therapy ; Coronavirus Infections/virology ; Exonucleases ; Humans ; Pandemics ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Exonucleases (EC 3.1.-) ; Alanine (OF5P57N2ZX)
    Keywords covid19
    Language English
    Publishing date 2020-04-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.H120.013397
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Halting coronavirus polymerase

    Kirchdoerfer, Robert N

    J Biol Chem

    Abstract: The nucleotide analogue remdesivir is an investigational drug for the treatment of human coronavirus infection. Remdesivir is a phosphoramidate prodrug and is known to target viral RNA-dependent RNA polymerases. In this issue, Gordon et al. identify that ...

    Abstract The nucleotide analogue remdesivir is an investigational drug for the treatment of human coronavirus infection. Remdesivir is a phosphoramidate prodrug and is known to target viral RNA-dependent RNA polymerases. In this issue, Gordon et al. identify that remdesivir acts as a delayed RNA chain terminator for MERS-CoV polymerase complexes.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #686585
    Database COVID19

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  3. Article ; Online: Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors.

    Kirchdoerfer, Robert N / Ward, Andrew B

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 2342

    Abstract: Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins ( ... ...

    Abstract Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV nsp12 polymerase bound to its essential co-factors, nsp7 and nsp8, using single particle cryo-electron microscopy. nsp12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is bound by two nsp8 co-factors. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity and acts as a template for the design of novel antiviral therapeutics.
    MeSH term(s) Coenzymes/ultrastructure ; Cryoelectron Microscopy ; DNA-Directed RNA Polymerases/ultrastructure ; Genome, Viral ; Severe acute respiratory syndrome-related coronavirus/metabolism ; Severe acute respiratory syndrome-related coronavirus/ultrastructure ; Viral Nonstructural Proteins/ultrastructure
    Chemical Substances Coenzymes ; Viral Nonstructural Proteins ; DNA-Directed RNA Polymerases (EC 2.7.7.6)
    Keywords covid19
    Language English
    Publishing date 2019-05-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-10280-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: An alphacoronavirus polymerase structure reveals conserved replication factor functions.

    Anderson, Thomas K / Hoferle, Peter J / Chojnacki, Kennan J / Lee, Kenneth W / Coon, Joshua J / Kirchdoerfer, Robert N

    Nucleic acids research

    2024  

    Abstract: Coronaviruses are a diverse subfamily of viruses containing pathogens of humans and animals. This subfamily of viruses replicates their RNA genomes using a core polymerase complex composed of viral non-structural proteins: nsp7, nsp8 and nsp12. Most of ... ...

    Abstract Coronaviruses are a diverse subfamily of viruses containing pathogens of humans and animals. This subfamily of viruses replicates their RNA genomes using a core polymerase complex composed of viral non-structural proteins: nsp7, nsp8 and nsp12. Most of our understanding of coronavirus molecular biology comes from betacoronaviruses like SARS-CoV and SARS-CoV-2, the latter of which is the causative agent of COVID-19. In contrast, members of the alphacoronavirus genus are relatively understudied despite their importance in human and animal health. Here we have used cryo-electron microscopy to determine structures of the alphacoronavirus porcine epidemic diarrhea virus (PEDV) core polymerase complex bound to RNA. One structure shows an unexpected nsp8 stoichiometry despite remaining bound to RNA. Biochemical analysis shows that the N-terminal extension of one nsp8 is not required for in vitro RNA synthesis for alpha- and betacoronaviruses. Our work demonstrates the importance of studying diverse coronaviruses in revealing aspects of coronavirus replication and identifying areas of conservation to be targeted by antiviral drugs.
    Language English
    Publishing date 2024-03-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkae153
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article: An alphacoronavirus polymerase structure reveals conserved co-factor functions.

    Anderson, Thomas K / Hoferle, Peter J / Lee, Kenneth W / Coon, Joshua J / Kirchdoerfer, Robert N

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Coronaviruses are a diverse subfamily of viruses containing pathogens of humans and animals. This subfamily of viruses replicates their RNA genomes using a core polymerase complex composed of viral non-structural proteins: nsp7, nsp8 and nsp12. Most of ... ...

    Abstract Coronaviruses are a diverse subfamily of viruses containing pathogens of humans and animals. This subfamily of viruses replicates their RNA genomes using a core polymerase complex composed of viral non-structural proteins: nsp7, nsp8 and nsp12. Most of our understanding of coronavirus molecular biology comes from the betacoronaviruses like SARS-CoV and SARS-CoV-2, the latter of which is the causative agent of COVID-19. In contrast, members of the alphacoronavirus genus are relatively understudied despite their importance in human and animal health. Here we have used cryo-electron microscopy to determine the structure of the alphacoronavirus porcine epidemic diarrhea virus (PEDV) core polymerase complex bound to RNA. Our structure shows an unexpected nsp8 stoichiometry in comparison to other published coronavirus polymerase structures. Biochemical analysis shows that the N-terminal extension of one nsp8 is not required for
    Language English
    Publishing date 2023-03-16
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.15.532841
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Mass spectrometric based detection of protein nucleotidylation in the RNA polymerase of SARS-CoV-2.

    Conti, Brian J / Leicht, Andrew S / Kirchdoerfer, Robert N / Sussman, Michael R

    Communications chemistry

    2021  Volume 4

    Abstract: Coronaviruses, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), encode a nucleotidyl transferase in the N-terminal (NiRAN) domain of the nonstructural protein (nsp) 12 protein within the RNA dependent RNA polymerase. Here we show the ... ...

    Abstract Coronaviruses, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), encode a nucleotidyl transferase in the N-terminal (NiRAN) domain of the nonstructural protein (nsp) 12 protein within the RNA dependent RNA polymerase. Here we show the detection of guanosine monophosphate (GMP) and uridine monophosphate-modified amino acids in nidovirus proteins using heavy isotope-assisted mass spectrometry (MS) and MS/MS peptide sequencing. We identified lysine-143 in the equine arteritis virus (EAV) protein, nsp7, as a primary site of in vitro GMP attachment via a phosphoramide bond. In SARS-CoV-2 replicase proteins, we demonstrate nsp12-mediated nucleotidylation of nsp7 lysine-2. Our results demonstrate new strategies for detecting GMP-peptide linkages that can be adapted for higher throughput screening using mass spectrometric technologies. These data are expected to be important for a rapid and timely characterization of a new enzymatic activity in SARS-CoV-2 that may be an attractive drug target aimed at limiting viral replication in infected patients.
    Language English
    Publishing date 2021-03-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2929562-2
    ISSN 2399-3669 ; 2399-3669
    ISSN (online) 2399-3669
    ISSN 2399-3669
    DOI 10.1038/s42004-021-00476-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Mass spectrometric based detection of protein nucleotidylation in the RNA polymerase of SARS-CoV-2.

    Conti, Brian J / Leicht, Andrew S / Kirchdoerfer, Robert N / Sussman, Michael R

    Communications chemistry

    2021  Volume 4, Issue 1, Page(s) 41

    Abstract: Coronaviruses, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), encode a nucleotidyl transferase in the N-terminal (NiRAN) domain of the nonstructural protein (nsp) 12 protein within the RNA dependent RNA polymerase. Here we show the ... ...

    Abstract Coronaviruses, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), encode a nucleotidyl transferase in the N-terminal (NiRAN) domain of the nonstructural protein (nsp) 12 protein within the RNA dependent RNA polymerase. Here we show the detection of guanosine monophosphate (GMP) and uridine monophosphate-modified amino acids in nidovirus proteins using heavy isotope-assisted mass spectrometry (MS) and MS/MS peptide sequencing. We identified lysine-143 in the equine arteritis virus (EAV) protein, nsp7, as a primary site of in vitro GMP attachment via a phosphoramide bond. In SARS-CoV-2 replicase proteins, we demonstrate nsp12-mediated nucleotidylation of nsp7 lysine-2. Our results demonstrate new strategies for detecting GMP-peptide linkages that can be adapted for higher throughput screening using mass spectrometric technologies. These data are expected to be important for a rapid and timely characterization of a new enzymatic activity in SARS-CoV-2 that may be an attractive drug target aimed at limiting viral replication in infected patients.
    Language English
    Publishing date 2021-03-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2929562-2
    ISSN 2399-3669 ; 2399-3669
    ISSN (online) 2399-3669
    ISSN 2399-3669
    DOI 10.1038/s42004-021-00476-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Cryo-EM structure of the Ebola virus nucleoprotein-RNA complex.

    Kirchdoerfer, Robert N / Saphire, Erica Ollmann / Ward, Andrew B

    Acta crystallographica. Section F, Structural biology communications

    2019  Volume 75, Issue Pt 5, Page(s) 340–347

    Abstract: Ebola virus is an emerging virus that is capable of causing a deadly disease in humans. Replication, transcription and packaging of the viral genome are carried out by the viral nucleocapsid. The nucleocapsid is a complex of the viral nucleoprotein, RNA ... ...

    Abstract Ebola virus is an emerging virus that is capable of causing a deadly disease in humans. Replication, transcription and packaging of the viral genome are carried out by the viral nucleocapsid. The nucleocapsid is a complex of the viral nucleoprotein, RNA and several other viral proteins. The nucleoprotein forms large, RNA-bound, helical filaments and acts as a scaffold for additional viral proteins. The 3.1 Å resolution single-particle cryo-electron microscopy structure of the nucleoprotein-RNA helical filament presented here resembles previous structures determined at lower resolution, while providing improved molecular details of protein-protein and protein-RNA interactions. The higher resolution of the structure presented here will facilitate the design and characterization of novel and specific Ebola virus therapeutics targeting the nucleocapsid.
    MeSH term(s) Amino Acid Sequence ; Binding Sites ; Cloning, Molecular ; Cryoelectron Microscopy ; Ebolavirus/chemistry ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; HEK293 Cells ; Humans ; Models, Molecular ; Nucleic Acid Conformation ; Nucleocapsid/chemistry ; Nucleocapsid/ultrastructure ; Nucleoproteins/chemistry ; Nucleoproteins/genetics ; Nucleoproteins/metabolism ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Interaction Domains and Motifs ; RNA, Viral/chemistry ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism
    Chemical Substances Nucleoproteins ; RNA, Viral ; Recombinant Proteins ; Viral Proteins
    Language English
    Publishing date 2019-04-24
    Publishing country United States
    Document type Journal Article
    ISSN 2053-230X
    ISSN (online) 2053-230X
    DOI 10.1107/S2053230X19004424
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Structure of the SARS-CoV NSP12 polymerase bound to NSP7 and NSP8 co-factors

    Kirchdoerfer, Robert N. / Ward, Andrew B.

    bioRxiv

    Abstract: Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins ( ... ...

    Abstract Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (NSP) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV NSP12 polymerase bound to its essential co-factors, NSP7 and NSP8, using single particle cryo-electron microscopy. NSP12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is unexpectedly bound by two NSP8 co-factors. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into NSP12 polymerase catalysis and fidelity and acts as a template for the design of novel antiviral therapeutics.
    Keywords covid19
    Publisher BioRxiv; MedRxiv
    Document type Article ; Online
    DOI 10.1101/551986
    Database COVID19

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  10. Article ; Online: An alphacoronavirus polymerase structure reveals conserved co-factor functions

    Anderson, Thomas K / Hoferle, Peter J / Lee, Kenneth W / Coon, Joshua J / Kirchdoerfer, Robert N

    bioRxiv

    Abstract: Coronaviruses are a diverse subfamily of viruses containing pathogens of humans and animals. This subfamily of viruses replicates their RNA genomes using a core polymerase complex composed of viral non-structural proteins: nsp7, nsp8 and nsp12. Most of ... ...

    Abstract Coronaviruses are a diverse subfamily of viruses containing pathogens of humans and animals. This subfamily of viruses replicates their RNA genomes using a core polymerase complex composed of viral non-structural proteins: nsp7, nsp8 and nsp12. Most of our understanding of coronavirus molecular biology comes from the betacoronaviruses like SARS-CoV and SARS-CoV-2, the latter of which is the causative agent of COVID-19. In contrast, members of the alphacoronavirus genus are relatively understudied despite their importance in human and animal health. Here we have used cryo-electron microscopy to determine the structure of the alphacoronavirus porcine epidemic diarrhea virus (PEDV) core polymerase complex bound to RNA. Our structure shows an unexpected nsp8 stoichiometry in comparison to other published coronavirus polymerase structures. Biochemical analysis shows that the N-terminal extension of one nsp8 is not required for in vitro RNA synthesis for alpha and betacoronaviruses as previously hypothesized. Our work shows the importance of studying diverse coronaviruses to reveal aspects of coronavirus replication while also identifying areas of conservation to be targeted by antiviral drugs.
    Keywords covid19
    Language English
    Publishing date 2023-03-16
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2023.03.15.532841
    Database COVID19

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