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Role of ATP in the RNA Translocation Mechanism of SARS-CoV-2 NSP13 Helicase.
Weber, Ryan; McCullagh, Martin.
  • Weber R; Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
  • McCullagh M; Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74074, United States.
J Phys Chem B ; 125(31): 8787-8796, 2021 08 12.
Article in English | MEDLINE | ID: covidwho-1333870
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ABSTRACT
The COVID-19 pandemic has demonstrated the need to develop potent and transferable therapeutics to treat coronavirus infections. Numerous antiviral targets are being investigated, but nonstructural protein 13 (nsp13) stands out as a highly conserved and yet understudied target. Nsp13 is a superfamily 1 (SF1) helicase that translocates along and unwinds viral RNA in an ATP-dependent manner. Currently, there are no available structures of nsp13 from SARS-CoV-1 or SARS-CoV-2 with either ATP or RNA bound, which presents a significant hurdle to the rational design of therapeutics. To address this knowledge gap, we have built models of SARS-CoV-2 nsp13 in Apo, ATP, ssRNA and ssRNA+ATP substrate states. Using 30 µs of a Gaussian-accelerated molecular dynamics simulation (at least 6 µs per substrate state), these models were confirmed to maintain substrate binding poses that are similar to other SF1 helicases. A Gaussian mixture model and linear discriminant analysis structural clustering protocol was used to identify key structural states of the ATP-dependent RNA translocation mechanism. Namely, four RNA-nsp13 structures are identified that exhibit ATP-dependent populations and support the inchworm mechanism for translocation. These four states are characterized by different RNA-binding poses for motifs Ia, IV, and V and suggest a power stroke-like motion of domain 2A relative to domain 1A. This structural and mechanistic insight of nsp13 RNA translocation presents novel targets for the further development of antivirals.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: J Phys Chem B Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jpcb.1c04528

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: J Phys Chem B Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jpcb.1c04528