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| | ==Structural Basis of Substrate Specificity and Protease Inhibition in Norwalk Virus== | | ==Structural Basis of Substrate Specificity and Protease Inhibition in Norwalk Virus== |
| | <StructureSection load='4inh' size='340' side='right' caption='[[4inh]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='4inh' size='340' side='right' caption='[[4inh]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4inh]] is a 16 chain structure with sequence from [http://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=4INH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4INH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4inh]] is a 16 chain structure with sequence from [http://en.wikipedia.org/wiki/Hu/nv/nv/1968/us Hu/nv/nv/1968/us]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4INH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4INH FirstGlance]. <br> |
| | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> | | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> |
| | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=1HB:(4S)-4-AMINO-5-HYDROXY-N,N-DIMETHYLPENTANAMIDE'>1HB</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr> | | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=1HB:(4S)-4-AMINO-5-HYDROXY-N,N-DIMETHYLPENTANAMIDE'>1HB</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr> |
| | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4imq|4imq]], [[4imz|4imz]], [[4in2|4in2]], [[4in1|4in1]]</td></tr> | | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4imq|4imq]], [[4imz|4imz]], [[4in2|4in2]], [[4in1|4in1]]</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ORF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=524364 Norovirus Hu/1968/US])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ORF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=524364 Hu/NV/NV/1968/US])</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=4inh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4inh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4inh RCSB], [http://www.ebi.ac.uk/pdbsum/4inh PDBsum]</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=4inh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4inh OCA], [http://pdbe.org/4inh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4inh RCSB], [http://www.ebi.ac.uk/pdbsum/4inh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4inh ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4inh" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Norovirus hu/1968/us]] | + | [[Category: Hu/nv/nv/1968/us]] |
| | [[Category: Deng, L]] | | [[Category: Deng, L]] |
| | [[Category: Estes, M K]] | | [[Category: Estes, M K]] |
| Structural highlights
Function
[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.[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 PubMed
Norwalk virus (NV), the prototype human calicivirus, is the leading cause of non-bacterial acute gastroenteritis. The NV protease cleaves the polyprotein, encoded by the open reading frame 1 of the viral genome, at five non-homologous sites to release six nonstructural proteins that are essential for viral replication. The structural details of how NV protease recognizes multiple substrates are unclear. In our X-ray structure of an NV protease construct, we observed that the C-terminal tail, representing a native substrate P5-P1, is inserted into the active site cleft of the neighboring protease molecule providing atomic details of how NV protease recognizes a substrate. The crystallographic structure of NV protease with the C-terminal tail redesigned to mimic P4-P1 of another substrate site provided further structural details of how the active site accommodates sequence variations in the substrates. Based on these structural analyses, substrate-based aldehyde inhibitors were synthesized and screened for their inhibition potency. Crystallographic structures of the protease in complex with each of the three most potent inhibitors were determined. These structures showed concerted conformational changes in the S4-S2 pockets of the protease to accommodate variations in the P4-P2 residues of the substrate/inhibitor, which could be a mechanism for how the NV protease recognizes multiple sites in the polyprotein with differential affinities during virus replication. These structures further indicate that the mechanism of inhibition by these inhibitors involves covalent bond formation with the side-chain of the conserved cysteine in the active site by nucleophilic addition, and such substrate-based aldehydes could be effective protease inhibitors.
Structural Basis of Substrate Specificity and Protease Inhibition in Norwalk Virus.,Muhaxhiri Z, Deng L, Shanker S, Sankaran B, Estes MK, Palzkill T, Song Y, Prasad BV J Virol. 2013 Jan 30. PMID:23365454[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Muhaxhiri Z, Deng L, Shanker S, Sankaran B, Estes MK, Palzkill T, Song Y, Prasad BV. Structural Basis of Substrate Specificity and Protease Inhibition in Norwalk Virus. J Virol. 2013 Jan 30. PMID:23365454 doi:http://dx.doi.org/10.1128/JVI.02869-12
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