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Crystal structure of the RNA-dependent RNA polymerase from influenza C virus

DOI: 10.1038/nature15525 DOI Help
PMID: 26503046 PMID Help

Authors: Narin Hengrung (University of Oxford) , Kamel El Omari (University of Oxford) , Itziar Serna Martin (University of Oxford) , Frank T. Vreede (University of Oxford) , Stephen Cusack (European Molecular Biology Laboratory) , Robert P. Rambo (Diamond Light Source) , Clemens Vonrhein (Global Phasing Ltd) , Gérard Bricogne (Global Phasing Ltd) , David I. Stuart (Diamond Light Source) , Jonathan M. Grimes (Diamond Light Source) , Ervin Fodor (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 527 (7576) , PAGES 114 - 117

State: Published (Approved)
Published: October 2015
Diamond Proposal Number(s): 8423

Abstract: Negative-sense RNA viruses, such as influenza, encode large, multidomain RNA-dependent RNA polymerases that can both transcribe and replicate the viral RNA genome1. In influenza virus, the polymerase (FluPol) is composed of three polypeptides: PB1, PB2 and PA/P3. PB1 houses the polymerase active site, whereas PB2 and PA/P3 contain, respectively, cap-binding and endonuclease domains required for transcription initiation by cap-snatching2. Replication occurs through de novo initiation and involves a complementary RNA intermediate. Currently available structures of the influenza A and B virus polymerases include promoter RNA (the 5′ and 3′ termini of viral genome segments), showing FluPol in transcription pre-initiation states3, 4. Here we report the structure of apo-FluPol from an influenza C virus, solved by X-ray crystallography to 3.9 Å, revealing a new ‘closed’ conformation. The apo-FluPol forms a compact particle with PB1 at its centre, capped on one face by PB2 and clamped between the two globular domains of P3. Notably, this structure is radically different from those of promoter-bound FluPols3, 4. The endonuclease domain of P3 and the domains within the carboxy-terminal two-thirds of PB2 are completely rearranged. The cap-binding site is occluded by PB2, resulting in a conformation that is incompatible with transcription initiation. Thus, our structure captures FluPol in a closed, transcription pre-activation state. This reveals the conformation of newly made apo-FluPol in an infected cell, but may also apply to FluPol in the context of a non-transcribing ribonucleoprotein complex. Comparison of the apo-FluPol structure with those of promoter-bound FluPols allows us to propose a mechanism for FluPol activation. Our study demonstrates the remarkable flexibility of influenza virus RNA polymerase, and aids our understanding of the mechanisms controlling transcription and genome replication.

Journal Keywords: Influenza virus

Subject Areas: Biology and Bio-materials

Instruments: B21-High Throughput SAXS , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

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