4o4r
Murine Norovirus RdRp in complex with PPNDS
Structural highlights
FunctionPOLG_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 PubMedNorovirus (NV) is a major cause of gastroenteritis worldwide. Antivirals against such important pathogens are on demand. Among the viral proteins that orchestrate viral replication, RNA-dependent-RNA-polymerase (RdRp) is a promising drug development target. From an in silico-docking search focused on the RdRp active site, we selected the compound PPNDS, which showed low micromolar IC50vs. murine NV-RdRp in vitro. We report the crystal structure of the murine NV-RdRp/PPNDS complex showing that two molecules of the inhibitor bind in antiparallel stacking interaction, properly oriented to block exit of the newly synthesized RNA. Such inhibitor-binding mode mimics two stacked nucleotide-bases of the RdRp/ssRNA complex. PPNDS inhibits murine Norovirus RNA-dependent RNA-polymerase mimicking two RNA stacking bases.,Croci R, Tarantino D, Milani M, Pezzullo M, Rohayem J, Bolognesi M, Mastrangelo E FEBS Lett. 2014 May 2;588(9):1720-5. doi: 10.1016/j.febslet.2014.03.021. Epub, 2014 Mar 18. PMID:24657439[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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