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4xbb

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Revision as of 09:33, 22 November 2017

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

Structural highlights

4xbb is a 1 chain structure with sequence from Hu/nv/nv/1968/us. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4xbc, 4xbd
Gene:	ORF1 (Hu/NV/NV/1968/US)
Activity:	Calicivirin, with EC number 3.4.22.66
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4xbb"

@@ Line 3: / Line 3: @@
 <StructureSection load='4xbb' size='340' side='right' caption='[[4xbb]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
 == 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 [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=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>
 </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>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xbc|4xbc]], [[4xbd|4xbd]]</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='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=4xbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xbb OCA], [http://pdbe.org/4xbb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xbb RCSB], [http://www.ebi.ac.uk/pdbsum/4xbb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xbb ProSAT]</span></td></tr>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 4xbb" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[RNA-directed RNA polymerase|RNA-directed RNA polymerase]]
 == References ==
 <references/>
@@ Line 28: / Line 26: @@
 </StructureSection>
 [[Category: Calicivirin]]
+[[Category: Hu/nv/nv/1968/us]]
 [[Category: Alliston, K R]]
 [[Category: Battaile, K P]]

4xbb

From Proteopedia

Revision as of 09:33, 22 November 2017

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

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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