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4nru
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 4nru is ON HOLD Authors: Milani, M., Croci, R., Pezzullo, M., Tarantino, D., Mastrangelo, E., Bolognesi, M. Description: Murine Norovirus RNA-depen...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Murine Norovirus RNA-dependent-RNA-polymerase in complex with Compound 6, a suramin derivative== | |
| + | <StructureSection load='4nru' size='340' side='right'caption='[[4nru]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4nru]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Murine_norovirus_1 Murine norovirus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NRU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NRU FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2NG:4-({4-METHYL-3-[(3-NITROBENZOYL)AMINO]BENZOYL}AMINO)NAPHTHALENE-1,5-DISULFONIC+ACID'>2NG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4nru FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nru OCA], [https://pdbe.org/4nru PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nru RCSB], [https://www.ebi.ac.uk/pdbsum/4nru PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nru ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/POLG_MNV1 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]<ref>PMID:28698274</ref> 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).<ref>PMID:23077309</ref> <ref>PMID:31130511</ref> <ref>PMID:31329638</ref> 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]<ref>PMID:30265237</ref> <ref>PMID:31905230</ref> <ref>PMID:36991121</ref> 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]<ref>PMID:16835235</ref> <ref>PMID:24928504</ref> <ref>PMID:30038601</ref> 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).<ref>PMID:26363064</ref> <ref>PMID:27147742</ref> 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] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Noroviruses (NV) are +ssRNA viruses responsible for severe gastroenteritis; no effective vaccines/antivirals are currently available. We previously identified Suramin (9) as a potent inhibitor of NV-RNA dependent RNA polymerase (NV-RdRp). Despite significant in vitro activities versus several pharmacological targets, Suramin clinical use is hampered by pharmacokinetics/toxicity problems. To improve Suramin access to NV-RdRp in vivo, a Suramin-derivative, 8, devoid of two sulphonate groups, was synthesized, achieving significant anti-human-NV-RdRp activity (IC50 = 28 nM); the compound inhibits also murine NV (mNV) RdRp. The synthesis process led to the isolation/characterization of lower molecular weight intermediates (3-7) hosting only one sulphonate head. The crystal structures of both hNV/mNV-RdRps in complex with 6, were analyzed, providing new knowledge on the interactions that a small fragment can establish with NV-RdRps, and establishing a platform for structure-guided optimization of potency, selectivity and drugability. | ||
| - | + | Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds.,Croci R, Pezzullo M, Tarantino D, Milani M, Tsay SC, Sureshbabu R, Tsai YJ, Mastrangelo E, Rohayem J, Bolognesi M, Hwu JR PLoS One. 2014 Mar 12;9(3):e91765. doi: 10.1371/journal.pone.0091765. eCollection, 2014. PMID:24622391<ref>PMID:24622391</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| + | <div class="pdbe-citations 4nru" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[RNA polymerase 3D structures|RNA polymerase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Murine norovirus 1]] | ||
| + | [[Category: Bolognesi M]] | ||
| + | [[Category: Croci R]] | ||
| + | [[Category: Mastrangelo E]] | ||
| + | [[Category: Milani M]] | ||
| + | [[Category: Pezzullo M]] | ||
| + | [[Category: Tarantino D]] | ||
Current revision
Murine Norovirus RNA-dependent-RNA-polymerase in complex with Compound 6, a suramin derivative
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