4xbd
From Proteopedia
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| - | ''' | + | ==1.45A 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 (Orthorhombic P Form)== |
| + | <StructureSection load='4xbd' size='340' side='right' caption='[[4xbd]], [[Resolution|resolution]] 1.45Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4xbd]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XBD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XBD FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xbb|4xbb]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Calicivirin Calicivirin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.66 3.4.22.66] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xbd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xbd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xbd RCSB], [http://www.ebi.ac.uk/pdbsum/4xbd PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://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> | |
| - | + | </div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| - | [[Category: Chang, K | + | [[Category: Calicivirin]] |
| - | [[Category: | + | [[Category: Alliston, K R]] |
| - | [[Category: | + | [[Category: Battaile, K P]] |
| - | [[Category: | + | [[Category: Chang, K O]] |
| - | [[Category: | + | [[Category: Damalanka, V C]] |
| + | [[Category: Groutas, W C]] | ||
| + | [[Category: Kankanamalage, A C.G]] | ||
| + | [[Category: Kim, Y]] | ||
[[Category: Lovell, S]] | [[Category: Lovell, S]] | ||
| - | [[Category: | + | [[Category: Mandadapu, S R]] |
| - | + | ||
[[Category: Mehzabeen, N]] | [[Category: Mehzabeen, N]] | ||
| - | [[Category: | + | [[Category: Uy, R A.Z]] |
| + | [[Category: Weerawarna, P M]] | ||
| + | [[Category: Antiviral inhibitor]] | ||
| + | [[Category: Dipeptidyl inhibitor]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
| + | [[Category: Norovirus]] | ||
| + | [[Category: Norwalk virus]] | ||
| + | [[Category: Protease]] | ||
Revision as of 13:56, 26 March 2015
1.45A 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 (Orthorhombic P Form)
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Categories: Calicivirin | Alliston, K R | Battaile, K P | Chang, K O | Damalanka, V C | Groutas, W C | Kankanamalage, A C.G | Kim, Y | Lovell, S | Mandadapu, S R | Mehzabeen, N | Uy, R A.Z | Weerawarna, P M | Antiviral inhibitor | Dipeptidyl inhibitor | Hydrolase-hydrolase inhibitor complex | Norovirus | Norwalk virus | Protease
