6w5h: Difference between revisions
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<StructureSection load='6w5h' size='340' side='right'caption='[[6w5h]], [[Resolution|resolution]] 1.85Å' scene=''> | <StructureSection load='6w5h' size='340' side='right'caption='[[6w5h]], [[Resolution|resolution]] 1.85Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6w5h]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6w5h]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Norovirus_Hu/1968/US Norovirus Hu/1968/US]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W5H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W5H FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TKP:2-(3-chlorophenyl)-2-methylpropyl+[(2S)-3-cyclohexyl-1-({(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-1-oxopropan-2-yl]carbamate'>TKP</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TKP:2-(3-chlorophenyl)-2-methylpropyl+[(2S)-3-cyclohexyl-1-({(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-1-oxopropan-2-yl]carbamate'>TKP</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=6w5h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w5h OCA], [https://pdbe.org/6w5h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w5h RCSB], [https://www.ebi.ac.uk/pdbsum/6w5h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w5h ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/POLG_NVN68 POLG_NVN68] Protein p48 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.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> Protein P22 may play a role in targeting replication complex to intracellular membranes.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave host polyadenylate-binding protein thereby inhibiting cellular translation (By similarity).<ref>PMID:569187</ref> <ref>PMID:11160659</ref> RNA-directed RNA polymerase 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 encodes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).<ref>PMID:569187</ref> <ref>PMID:11160659</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6w5h" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6w5h" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Virus protease 3D structures|Virus protease 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Battaile | [[Category: Norovirus Hu/1968/US]] | ||
[[Category: Chang | [[Category: Battaile KP]] | ||
[[Category: Groutas | [[Category: Chang KO]] | ||
[[Category: Kashipathy | [[Category: Groutas WC]] | ||
[[Category: Kim | [[Category: Kashipathy MM]] | ||
[[Category: Lovell | [[Category: Kim Y]] | ||
[[Category: Rathnayake | [[Category: Lovell S]] | ||
[[Category: Rathnayake AD]] | |||
Revision as of 17:17, 18 October 2023
1.85 A resolution structure of Norovirus 3CL protease in complex with inhibitor 5d1.85 A resolution structure of Norovirus 3CL protease in complex with inhibitor 5d
Structural highlights
FunctionPOLG_NVN68 Protein p48 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.[1] [2] NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity.[3] [4] Protein P22 may play a role in targeting replication complex to intracellular membranes.[5] [6] Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation.[7] [8] 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave host polyadenylate-binding protein thereby inhibiting cellular translation (By similarity).[9] [10] RNA-directed RNA polymerase 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 encodes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).[11] [12] Publication Abstract from PubMedAcute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the gem-dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the gem-dimethyl group. Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease.,Rathnayake AD, Kim Y, Dampalla CS, Nguyen HN, Jesri AM, Kashipathy MM, Lushington GH, Battaile KP, Lovell S, Chang KO, Groutas WC J Med Chem. 2020 Sep 18. doi: 10.1021/acs.jmedchem.0c01252. PMID:32945669[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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