5e0h: Difference between revisions
New page: '''Unreleased structure''' The entry 5e0h is ON HOLD Authors: Lovell, Scott, Battaile, Kevin P., Mehzabeen, Nurjahan, Weerawarna, Pathum M., Kim, Yunjeong, Kankanamalage, Anushka C.Gala... |
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==1.95 A resolution structure of Norovirus 3CL protease in complex with a triazole-based macrocyclic (18-mer) inhibitor== | |||
<StructureSection load='5e0h' size='340' side='right'caption='[[5e0h]], [[Resolution|resolution]] 1.95Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5e0h]] is a 2 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=5E0H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E0H 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]] 1.95Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5LH:(PHENYLMETHYL)+~{N}-[(9~{S},12~{S},15~{S})-9-(HYDROXYMETHYL)-12-(2-METHYLPROPYL)-6,11,14-TRIS(OXIDANYLIDENE)-1,5,10,13,18,19-HEXAZABICYCLO[15.2.1]ICOSA-17(20),18-DIEN-15-YL]CARBAMATE'>5LH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=5e0h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e0h OCA], [https://pdbe.org/5e0h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e0h RCSB], [https://www.ebi.ac.uk/pdbsum/5e0h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e0h ProSAT]</span></td></tr> | |||
</table> | |||
== 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;"> | |||
== Publication Abstract from PubMed == | |||
Outbreaks of acute gastroenteritis caused by noroviruses constitute a public health concern worldwide. To date, there are no approved drugs or vaccines for the management and prophylaxis of norovirus infections. A potentially effective strategy for the development of norovirus therapeutics entails the discovery of inhibitors of norovirus 3CL protease, an enzyme essential for noroviral replication. We describe herein the structure-based design of the first class of permeable, triazole-based macrocyclic inhibitors of norovirus 3C-like protease, as well as pertinent X-ray crystallographic, biochemical, spectroscopic, and antiviral studies. | |||
Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies.,Weerawarna PM, Kim Y, Galasiti Kankanamalage AC, Damalanka VC, Lushington GH, Alliston KR, Mehzabeen N, Battaile KP, Lovell S, Chang KO, Groutas WC Eur J Med Chem. 2016 Aug 25;119:300-18. doi: 10.1016/j.ejmech.2016.04.013. Epub, 2016 Apr 25. PMID:27235842<ref>PMID:27235842</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5e0h" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Chang | ==See Also== | ||
[[Category: | *[[Virus protease 3D structures|Virus protease 3D structures]] | ||
[[Category: | == References == | ||
[[Category: Lovell | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Norovirus Hu/1968/US]] | |||
[[Category: Alliston KR]] | |||
[[Category: Battaile KP]] | |||
[[Category: Chang K-O]] | |||
[[Category: Damalanka VC]] | |||
[[Category: Groutas WC]] | |||
[[Category: Kankanamalage ACG]] | |||
[[Category: Kim Y]] | |||
[[Category: Lovell S]] | |||
[[Category: Lushington GH]] | |||
[[Category: Mehzabeen N]] | |||
[[Category: Weerawarna PM]] | |||
Latest revision as of 01:08, 29 June 2023
1.95 A resolution structure of Norovirus 3CL protease in complex with a triazole-based macrocyclic (18-mer) inhibitor1.95 A resolution structure of Norovirus 3CL protease in complex with a triazole-based macrocyclic (18-mer) inhibitor
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 PubMedOutbreaks of acute gastroenteritis caused by noroviruses constitute a public health concern worldwide. To date, there are no approved drugs or vaccines for the management and prophylaxis of norovirus infections. A potentially effective strategy for the development of norovirus therapeutics entails the discovery of inhibitors of norovirus 3CL protease, an enzyme essential for noroviral replication. We describe herein the structure-based design of the first class of permeable, triazole-based macrocyclic inhibitors of norovirus 3C-like protease, as well as pertinent X-ray crystallographic, biochemical, spectroscopic, and antiviral studies. Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies.,Weerawarna PM, Kim Y, Galasiti Kankanamalage AC, Damalanka VC, Lushington GH, Alliston KR, Mehzabeen N, Battaile KP, Lovell S, Chang KO, Groutas WC Eur J Med Chem. 2016 Aug 25;119:300-18. doi: 10.1016/j.ejmech.2016.04.013. Epub, 2016 Apr 25. PMID:27235842[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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