This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
4xbc
From Proteopedia
(Difference between revisions)
| (5 intermediate revisions not shown.) | |||
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==1.60 A resolution structure of Norovirus 3CL protease complex with a covalently bound dipeptidyl inhibitor (1R,2S)-2-({N-[(benzyloxy)carbonyl]-3-cyclohexyl-L-alanyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid (Hexagonal Form)== | |
| + | <StructureSection load='4xbc' size='340' side='right'caption='[[4xbc]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4xbc]] is a 1 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=4XBC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XBC FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=M40:(1R,2S)-2-({N-[(BENZYLOXY)CARBONYL]-3-CYCLOHEXYL-L-ALANYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>M40</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=4xbc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xbc OCA], [https://pdbe.org/4xbc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xbc RCSB], [https://www.ebi.ac.uk/pdbsum/4xbc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xbc 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 == | ||
| + | Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection. | ||
| - | + | Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure-Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies.,Galasiti Kankanamalage AC, Kim Y, Weerawarna PM, Uy RA, Damalanka VC, Mandadapu SR, Alliston KR, Mehzabeen N, Battaile KP, Lovell S, Chang KO, Groutas WC J Med Chem. 2015 Mar 19. PMID:25761614<ref>PMID:25761614</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Alliston | + | <div class="pdbe-citations 4xbc" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | |
| - | [[Category: | + | ==See Also== |
| - | [[Category: | + | *[[Virus protease 3D structures|Virus protease 3D structures]] |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: Mehzabeen | + | [[Category: Norovirus Hu/1968/US]] |
| - | [[Category: | + | [[Category: Alliston KR]] |
| - | [[Category: | + | [[Category: Battaile KP]] |
| + | [[Category: Chang K-O]] | ||
| + | [[Category: Damalanka VC]] | ||
| + | [[Category: Groutas WC]] | ||
| + | [[Category: Kankanamalage ACG]] | ||
| + | [[Category: Kim Y]] | ||
| + | [[Category: Lovell S]] | ||
| + | [[Category: Mandadapu SR]] | ||
| + | [[Category: Mehzabeen N]] | ||
| + | [[Category: Uy RAZ]] | ||
| + | [[Category: Weerawarna PM]] | ||
Current revision
1.60 A resolution structure of Norovirus 3CL protease complex with a covalently bound dipeptidyl inhibitor (1R,2S)-2-({N-[(benzyloxy)carbonyl]-3-cyclohexyl-L-alanyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid (Hexagonal Form)
| |||||||||||
