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Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex

Chen, James ; Malone, Brandon ; Llewellyn, Eliza ; Grasso, Michael ; Shelton, Patrick M.M. ; Olinares, Paul Dominic B. ; Maruthi, Kashyap ; Eng, Edward T. ; Vatandaslar, Hasan ; Chait, Brian T. ; Kapoor, Tarun M. ; Darst, Seth A. ; Campbell, Elizabeth A.

Cell, 2020-09, Vol.182 (6), p.1560-1573.e13 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex
Autor: Chen, James ; Malone, Brandon ; Llewellyn, Eliza ; Grasso, Michael ; Shelton, Patrick M.M. ; Olinares, Paul Dominic B. ; Maruthi, Kashyap ; Eng, Edward T. ; Vatandaslar, Hasan ; Chait, Brian T. ; Kapoor, Tarun M. ; Darst, Seth A. ; Campbell, Elizabeth A.
Assuntos: Adenosine Diphosphate - chemistry ; Adenosine Diphosphate - metabolism ; Adenosine triphosphatase ; Analysis ; Antiviral agents ; Betacoronavirus - genetics ; Betacoronavirus - metabolism ; Betacoronavirus - ultrastructure ; Binding Sites ; Cells ; Coronavirus RNA-Dependent RNA Polymerase ; Cryoelectron Microscopy ; Genetic transcription ; Health aspects ; Holoenzymes - chemistry ; Holoenzymes - metabolism ; Magnesium - metabolism ; Methyltransferases - chemistry ; Methyltransferases - metabolism ; Protein Binding ; RNA ; RNA Helicases - chemistry ; RNA Helicases - metabolism ; RNA, Viral - chemistry ; RNA-Dependent RNA Polymerase - chemistry ; RNA-Dependent RNA Polymerase - metabolism ; SARS-CoV-2 ; Viral Nonstructural Proteins - chemistry ; Viral Nonstructural Proteins - metabolism ; Virus Replication
É parte de: Cell, 2020-09, Vol.182 (6), p.1560-1573.e13
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These authors contributed equally
Descrição: SARS-CoV-2 is the causative agent of the 2019–2020 pandemic. The SARS-CoV-2 genome is replicated and transcribed by the RNA-dependent RNA polymerase holoenzyme (subunits nsp7/nsp82/nsp12) along with a cast of accessory factors. One of these factors is the nsp13 helicase. Both the holo-RdRp and nsp13 are essential for viral replication and are targets for treating the disease COVID-19. Here we present cryoelectron microscopic structures of the SARS-CoV-2 holo-RdRp with an RNA template product in complex with two molecules of the nsp13 helicase. The Nidovirales order-specific N-terminal domains of each nsp13 interact with the N-terminal extension of each copy of nsp8. One nsp13 also contacts the nsp12 thumb. The structure places the nucleic acid-binding ATPase domains of the helicase directly in front of the replicating-transcribing holo-RdRp, constraining models for nsp13 function. We also observe ADP-Mg2+ bound in the nsp12 N-terminal nidovirus RdRp-associated nucleotidyltransferase domain, detailing a new pocket for anti-viral therapy development. [Display omitted] •Structure of SARS-CoV-2 replication-transcription complex (RTC) with nsp13 helicases•The nsp13 NTPase domains sit in front of the RCT, constraining functional models•Nsp13 may drive RTC backtracking, affecting proofreading and template switching•Structural analysis of ADP-Mg2+-bound NiRAN domain, a potential antiviral target Chen et al. present cryo-EM structures of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) holoenzyme (nsp7/nsp8/nsp12) containing an RNA template product in complex with the viral helicase (nsp13). The work provides insight into assembly and function of the multi-subunit protein machine and how it might be targeted therapeutically to treat COVID-19.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex

Chen, James ; Malone, Brandon ; Llewellyn, Eliza ; Grasso, Michael ; Shelton, Patrick M.M. ; Olinares, Paul Dominic B. ; Maruthi, Kashyap ; Eng, Edward T. ; Vatandaslar, Hasan ; Chait, Brian T. ; Kapoor, Tarun M. ; Darst, Seth A. ; Campbell, Elizabeth A.

United States: Elsevier Inc

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