A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent

Klein M, Das A, Bera SC, Anderson TK, Kocincova D, Lee HW, Wang B, Papini FS, Marecki JC, Arnold JJ, Cameron CE, Raney KD, Artsimovitch I, Götte M, Kirchdoerfer RN, Depken M, Dulin D (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nucleic Acids Research Oxford University Press

Book Volume: 53

Article Number: gkaf450

Journal Issue: 10

DOI: 10.1093/nar/gkaf450

Abstract

Coronaviruses (CoVs) encode 16 nonstructural proteins (nsps), most of which form the replication-transcription complex (RTC). The RTC contains a core composed of one nsp12 RNA-dependent RNA polymerase (RdRp), two nsp8s, and one nsp7. The core RTC recruits other nsps to synthesize all viral RNAs within the infected cell. While essential for viral replication, the mechanism by which the core RTC assembles into a processive polymerase remains poorly understood. We show that the core RTC preferentially assembles by first having nsp12-polymerase bind to the RNA template, followed by the subsequent association of nsp7 and nsp8. Once assembled on the RNA template, the core RTC requires hundreds of seconds to undergo a conformational change that enables processive elongation. In the absence of RNA, the (apo-)RTC requires several hours to adopt its elongation-competent conformation. We propose that this obligatory activation step facilitates the recruitment of additional nsps essential for efficient viral RNA synthesis and may represent a promising target for therapeutic interventions.

Authors with CRIS profile

Subhas Chandra Bera Interdisziplinäres Zentrum für Klinische Forschung IZKF Nachwuchsgruppe 2 Prof. Dr. Dulin

Involved external institutions

University of North Carolina at Chapel Hill US United States (USA) (US) University of Arkansas for Medical Sciences (UAMS) US United States (USA) (US) Ohio State University US United States (USA) (US) University of Alberta CA Canada (CA) University of Wisconsin - Madison US United States (USA) (US) Delft University of Technology (TU Delft) NL Netherlands (NL) Vrije Universiteit Amsterdam (VU) / University Amsterdam NL Netherlands (NL)

How to cite

APA:

Klein, M., Das, A., Bera, S.C., Anderson, T.K., Kocincova, D., Lee, H.W.,... Dulin, D. (2025). A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent. Nucleic Acids Research, 53(10). https://doi.org/10.1093/nar/gkaf450

MLA:

Klein, Misha, et al. "A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent." Nucleic Acids Research 53.10 (2025).

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