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Structural Insights into Binding of Remdesivir Triphosphate within the Replication-Transcription Complex of SARS-CoV-2.
Wang, Jimin; Shi, Yuanjun; Reiss, Krystle; Maschietto, Federica; Lolis, Elias; Konigsberg, William H; Lisi, George P; Batista, Victor S.
  • Wang J; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8114, United States.
  • Shi Y; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8499, United States.
  • Reiss K; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8499, United States.
  • Maschietto F; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8499, United States.
  • Lolis E; Department of Pharmacology, Yale University, New Haven, Connecticut 06520-8066, United States.
  • Konigsberg WH; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8114, United States.
  • Lisi GP; Department of Molecular and Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02912, United States.
  • Batista VS; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8499, United States.
Biochemistry ; 61(18): 1966-1973, 2022 09 20.
Статья в английский | MEDLINE | ID: covidwho-2016509
ABSTRACT
Remdesivir is an adenosine analogue that has a cyano substitution in the C1' position of the ribosyl moiety and a modified base structure to stabilize the linkage of the base to the C1' atom with its strong electron-withdrawing cyano group. Within the replication-transcription complex (RTC) of SARS-CoV-2, the RNA-dependent RNA polymerase nsp12 selects remdesivir monophosphate (RMP) over adenosine monophosphate (AMP) for nucleotide incorporation but noticeably slows primer extension after the added RMP of the RNA duplex product is translocated by three base pairs. Cryo-EM structures have been determined for the RTC with RMP at the nucleotide-insertion (i) site or at the i + 1, i + 2, or i + 3 sites after product translocation to provide a structural basis for a delayed-inhibition mechanism by remdesivir. In this study, we applied molecular dynamics (MD) simulations to extend the resolution of structures to the measurable maximum that is intrinsically limited by MD properties of these complexes. Our MD simulations provide (i) a structural basis for nucleotide selectivity of the incoming substrates of remdesivir triphosphate over adenosine triphosphate and of ribonucleotide over deoxyribonucleotide, (ii) new detailed information on hydrogen atoms involved in H-bonding interactions between the enzyme and remdesivir, and (iii) direct information on the catalytically active complex that is not easily captured by experimental methods. Our improved resolution of interatomic interactions at the nucleotide-binding pocket between remedesivir and the polymerase could help to design a new class of anti-SARS-CoV-2 inhibitors.
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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: Antiviral Agents / Adenosine Triphosphate / SARS-CoV-2 Язык: английский Журнал: Biochemistry Год: 2022 Тип: Статья Аффилированная страна: Acs.biochem.2c00341

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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: Antiviral Agents / Adenosine Triphosphate / SARS-CoV-2 Язык: английский Журнал: Biochemistry Год: 2022 Тип: Статья Аффилированная страна: Acs.biochem.2c00341