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| | ==1.85A resolution structure of Norovirus 3CL protease complex with a covalently bound dipeptidyl inhibitor diethyl [(1R,2S)-2-[(N-{[(3-chlorobenzyl)oxy]carbonyl}-3-cyclohexyl-L-alanyl)amino]-1-hydroxy-3-(2-oxo-2H-pyrrol-3-yl)propyl]phosphonate== | | ==1.85A resolution structure of Norovirus 3CL protease complex with a covalently bound dipeptidyl inhibitor diethyl [(1R,2S)-2-[(N-{[(3-chlorobenzyl)oxy]carbonyl}-3-cyclohexyl-L-alanyl)amino]-1-hydroxy-3-(2-oxo-2H-pyrrol-3-yl)propyl]phosphonate== |
| - | <StructureSection load='4xbb' size='340' side='right' caption='[[4xbb]], [[Resolution|resolution]] 1.85Å' scene=''> | + | <StructureSection load='4xbb' size='340' side='right'caption='[[4xbb]], [[Resolution|resolution]] 1.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4xbb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XBB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XBB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4xbb]] 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=4XBB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XBB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3ZR:DIETHYL+[(1R,2S)-2-[(N-{[(3-CHLOROBENZYL)OXY]CARBONYL}-3-CYCLOHEXYL-L-ALANYL)AMINO]-1-HYDROXY-3-(2-OXO-2H-PYRROL-3-YL)PROPYL]PHOSPHONATE'>3ZR</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xbc|4xbc]], [[4xbd|4xbd]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3ZR:DIETHYL+[(1R,2S)-2-[(N-{[(3-CHLOROBENZYL)OXY]CARBONYL}-3-CYCLOHEXYL-L-ALANYL)AMINO]-1-HYDROXY-3-(2-OXO-2H-PYRROL-3-YL)PROPYL]PHOSPHONATE'>3ZR</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4xbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xbb OCA], [https://pdbe.org/4xbb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xbb RCSB], [https://www.ebi.ac.uk/pdbsum/4xbb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xbb ProSAT]</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=4xbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xbb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xbb RCSB], [http://www.ebi.ac.uk/pdbsum/4xbb PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [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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| | 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 4xbb" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[RNA-directed RNA polymerase|RNA-directed RNA polymerase]] |
| | + | *[[Virus protease 3D structures|Virus protease 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Calicivirin]] | + | [[Category: Large Structures]] |
| - | [[Category: Alliston, K R]] | + | [[Category: Norovirus Hu/1968/US]] |
| - | [[Category: Battaile, K P]] | + | [[Category: Alliston KR]] |
| - | [[Category: Chang, K O]] | + | [[Category: Battaile KP]] |
| - | [[Category: Damalanka, V C]] | + | [[Category: Chang K-O]] |
| - | [[Category: Groutas, W C]] | + | [[Category: Damalanka VC]] |
| - | [[Category: Kankanamalage, A C.G]] | + | [[Category: Groutas WC]] |
| - | [[Category: Kim, Y]] | + | [[Category: Kankanamalage ACG]] |
| - | [[Category: Lovell, S]] | + | [[Category: Kim Y]] |
| - | [[Category: Mandadapu, S R]] | + | [[Category: Lovell S]] |
| - | [[Category: Mehzabeen, N]] | + | [[Category: Mandadapu SR]] |
| - | [[Category: Uy, R A.Z]] | + | [[Category: Mehzabeen N]] |
| - | [[Category: Weerawarna, P M]] | + | [[Category: Uy RAZ]] |
| - | [[Category: Antiviral inhibitor]]
| + | [[Category: Weerawarna PM]] |
| - | [[Category: Dipeptidyl inhibitor]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Norovirus]]
| + | |
| - | [[Category: Norwalk virus]]
| + | |
| - | [[Category: Protease]]
| + | |
| 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
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[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ 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. 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. J Med Chem. 2015 Mar 19. PMID:25761614 doi:http://dx.doi.org/10.1021/jm5019934
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