3sfu

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crystal structure of murine norovirus RNA dependent RNA polymerase in complex with ribavirin

Structural highlights

3sfu is a 3 chain structure with sequence from Murine norovirus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.501Å
Ligands:GOL, MG, RBV, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

POLG_MNV1 Induces the proliferation of the host smooth ER membranes forming long tubular structures (By similarity). These remodeled membranes probably form the viral factories that contain the replication complex (By similarity). May play a role in viral replication by interacting with host VAPA, a vesicle-associated membrane protein that plays a role in SNARE-mediated vesicle fusion. This interaction may target replication complex to intracellular membranes (Probable).[UniProtKB:P54634][1] Promotes intestinal tropism and persistent fecal shedding in strain CR6 (PubMed:23077309, PubMed:31130511, PubMed:31329638). This function requires Glu-94 and is present in persistant strains (PubMed:23077309).[2] [3] [4] Displays NTPase activity, but probably no helicase activity (PubMed:30265237). Displays RNA chaperone-like activity and destabilizes dsRNA (PubMed:30265237). Induces the formation of convoluted membranes derived from the host ER (By similarity). These remodeled membranes probably form the viral factories that contain the replication complex (By similarity). Initiates host cell death by targeting the mitochondrial outer membrane, leading to the permeabilization of mitochondria, programmed host cell death and viral egress (PubMed:36991121). Externalization of host cardiolipin seems to be involved in the process (PubMed:36991121). Probably plays a role in preventing the assembly of host stress granules (PubMed:31905230).[UniProtKB:P54634][5] [6] [7] Probable key protein responsible for the formation of membrane alterations by the virus (By similarity). Induces the formation of convoluted membranes derived from the host ER (By similarity). These remodeled membranes probably form the viral factories that contain the replication complex (By similarity). May play a role in targeting replication complex to intracellular membranes.[UniProtKB:P54634] Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA (By similarity). Acts as a genome-linked replication primer (By similarity). May recruit ribosome to viral RNA thereby promoting viral proteins translation (By similarity). Interacts with host translation initiation complex to allow the translation of viral proteins (PubMed:16835235, PubMed:24928504). Induces the formation of aggregates of RNA-directed RNA polymerase in the presence of RNA (PubMed:30038601). Through its interaction with the viral RNA-directed RNA polymerase, plays a crucial role in enhancing the polymerase activity (PubMed:30038601).[UniProtKB:P27409][8] [9] [10] Processes the polyprotein. 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved (PubMed:26363064). May cleave host polyadenylate-binding protein thereby inhibiting cellular translation. Does not cleave host G3BP1 (PubMed:27147742).[11] [12] Replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This sgRNA codes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).[UniProtKB:Q86119]

Publication Abstract from PubMed

Murine norovirus-1 (MNV-1) shares many features with human norovirus (HuNoV) and both are classified within the norovirus genus of Caliciviridae family. MNV-1 is used as the surrogate for HuNoV research since it is the only form that can be grown in cell culture. HuNoV and MNV-1 RNA dependent RNA polymerase (RdRp) proteins with the sequence identity of 59% show essentially identical conformations. Here we report the first structural evidence of 2-thiouridine (2TU) or ribavirin binding to MNV-1 RdRp, based on the crystal structures determined at 2.2A and 2.5A resolutions, respectively. Cellular and biochemical studies revealed stronger inhibitory effect of 2TU on the replication of MNV-1 in RAW 264.7 cells, compared to that of ribavirin. Our complex structures highlight the key interactions involved in recognition of the nucleoside analogs which block the active site of the viral RNA polymerase.

Crystal structures of murine norovirus-1 RNA-dependent RNA polymerase in complex with 2-thiouridine or ribavirin.,Alam I, Lee JH, Cho KJ, Han KR, Yang JM, Chung MS, Kim KH Virology. 2012 May 10;426(2):143-51. Epub 2012 Feb 16. PMID:22341781[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. McCune BT, Tang W, Lu J, Eaglesham JB, Thorne L, Mayer AE, Condiff E, Nice TJ, Goodfellow I, Krezel AM, Virgin HW. Noroviruses Co-opt the Function of Host Proteins VAPA and VAPB for Replication via a Phenylalanine-Phenylalanine-Acidic-Tract-Motif Mimic in Nonstructural Viral Protein NS1/2. mBio. 2017 Jul 11;8(4):e00668-17. PMID:28698274 doi:10.1128/mBio.00668-17
  2. Nice TJ, Strong DW, McCune BT, Pohl CS, Virgin HW. A single-amino-acid change in murine norovirus NS1/2 is sufficient for colonic tropism and persistence. J Virol. 2013 Jan;87(1):327-34. PMID:23077309 doi:10.1128/JVI.01864-12
  3. Lee S, Liu H, Wilen CB, Sychev ZE, Desai C, Hykes BL Jr, Orchard RC, McCune BT, Kim KW, Nice TJ, Handley SA, Baldridge MT, Amarasinghe GK, Virgin HW. A Secreted Viral Nonstructural Protein Determines Intestinal Norovirus Pathogenesis. Cell Host Microbe. 2019 Jun 12;25(6):845-857.e5. PMID:31130511 doi:10.1016/j.chom.2019.04.005
  4. Robinson BA, Van Winkle JA, McCune BT, Peters AM, Nice TJ. Caspase-mediated cleavage of murine norovirus NS1/2 potentiates apoptosis and is required for persistent infection of intestinal epithelial cells. PLoS Pathog. 2019 Jul 22;15(7):e1007940. PMID:31329638 doi:10.1371/journal.ppat.1007940
  5. Han KR, Lee JH, Kotiguda GG, Jung KH, Chung MS, Kang S, Hwang S, Kim KH. Nucleotide triphosphatase and RNA chaperone activities of murine norovirus NS3. J Gen Virol. 2018 Nov;99(11):1482-1493. PMID:30265237 doi:10.1099/jgv.0.001151
  6. Brocard M, Iadevaia V, Klein P, Hall B, Lewis G, Lu J, Burke J, Willcocks MM, Parker R, Goodfellow IG, Ruggieri A, Locker N. Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation. PLoS Pathog. 2020 Jan 6;16(1):e1008250. PMID:31905230 doi:10.1371/journal.ppat.1008250
  7. Wang G, Zhang D, Orchard RC, Hancks DC, Reese TA. Norovirus MLKL-like protein initiates cell death to induce viral egress. Nature. 2023 Apr;616(7955):152-158. PMID:36991121 doi:10.1038/s41586-023-05851-w
  8. Chaudhry Y, Nayak A, Bordeleau ME, Tanaka J, Pelletier J, Belsham GJ, Roberts LO, Goodfellow IG. Caliciviruses differ in their functional requirements for eIF4F components. J Biol Chem. 2006 Sep 1;281(35):25315-25. PMID:16835235 doi:10.1074/jbc.M602230200
  9. Chung L, Bailey D, Leen EN, Emmott EP, Chaudhry Y, Roberts LO, Curry S, Locker N, Goodfellow IG. Norovirus translation requires an interaction between the C Terminus of the genome-linked viral protein VPg and eukaryotic translation initiation factor 4G. J Biol Chem. 2014 Aug 1;289(31):21738-50. PMID:24928504 doi:10.1074/jbc.M114.550657
  10. Lee JH, Park BS, Han KR, Biering SB, Kim SJ, Choi J, Seok JH, Alam I, Chung MS, Kim HM, Hwang S, Kim KH. Insight Into the Interaction Between RNA Polymerase and VPg for Murine Norovirus Replication. Front Microbiol. 2018 Jul 3;9:1466. doi: 10.3389/fmicb.2018.01466. eCollection, 2018. PMID:30038601 doi:http://dx.doi.org/10.3389/fmicb.2018.01466
  11. Emmott E, Sweeney TR, Goodfellow I. A Cell-based Fluorescence Resonance Energy Transfer (FRET) Sensor Reveals Inter- and Intragenogroup Variations in Norovirus Protease Activity and Polyprotein Cleavage. J Biol Chem. 2015 Nov 13;290(46):27841-53. PMID:26363064 doi:10.1074/jbc.M115.688234
  12. Humoud MN, Doyle N, Royall E, Willcocks MM, Sorgeloos F, van Kuppeveld F, Roberts LO, Goodfellow IG, Langereis MA, Locker N. Feline Calicivirus Infection Disrupts Assembly of Cytoplasmic Stress Granules and Induces G3BP1 Cleavage. J Virol. 2016 Jun 24;90(14):6489-6501. PMID:27147742 doi:10.1128/JVI.00647-16
  13. Alam I, Lee JH, Cho KJ, Han KR, Yang JM, Chung MS, Kim KH. Crystal structures of murine norovirus-1 RNA-dependent RNA polymerase in complex with 2-thiouridine or ribavirin. Virology. 2012 May 10;426(2):143-51. Epub 2012 Feb 16. PMID:22341781 doi:10.1016/j.virol.2012.01.016

Contents


PDB ID 3sfu

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