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4f49

From Proteopedia

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Current revision

2.25A resolution structure of Transmissible Gastroenteritis Virus Protease containing a covalently bound Dipeptidyl Inhibitor

Structural highlights

4f49 is a 4 chain structure with sequence from Porcine transmissible gastroenteritis coronavirus strain Purdue. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.25Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

R1A_CVPPU The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3 (By similarity). The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SAGC]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK. Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter (By similarity). Nsp9 is a ssRNA-binding protein (By similarity).

Publication Abstract from PubMed

Phylogenetic analysis has demonstrated that some positive sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively) which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as an attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We have previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, aldehyde (GC373), bisulfite adduct (GC376) and alpha-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses with the half maximal inhibitory concentration in the high nanomolar or low micromolar range in the enzyme and/or cell-based assays with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of the NV 3CLpro-, poliovirus 3Cpro- or transmissible gastroenteritis virus 3CLpro-inhibitor GC376 complex that show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.

Broad-Spectrum Antivirals against 3C or 3C-like Proteases of Picornaviruses, Noroviruses and Coronaviruses.,Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, Groutas WC, Chang KO J Virol. 2012 Aug 22. PMID:22915796^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, Groutas WC, Chang KO. Broad-Spectrum Antivirals against 3C or 3C-like Proteases of Picornaviruses, Noroviruses and Coronaviruses. J Virol. 2012 Aug 22. PMID:22915796 doi:http://dx.doi.org/10.1128/JVI.01348-12

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/4f49"

@@ Line 1: / Line 1: @@
 ==2.25A resolution structure of Transmissible Gastroenteritis Virus Protease containing a covalently bound Dipeptidyl Inhibitor==
-<StructureSection load='4f49' size='340' side='right' caption='[[4f49]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
+<StructureSection load='4f49' size='340' side='right'caption='[[4f49]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4f49]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Cvppu Cvppu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F49 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F49 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4f49]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Porcine_transmissible_gastroenteritis_coronavirus_strain_Purdue Porcine transmissible gastroenteritis coronavirus strain Purdue]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F49 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F49 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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]] 2.25&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">1a ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11151 CVPPU])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4f49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f49 OCA], [http://pdbe.org/4f49 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4f49 RCSB], [http://www.ebi.ac.uk/pdbsum/4f49 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4f49 ProSAT]</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=4f49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f49 OCA], [https://pdbe.org/4f49 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f49 RCSB], [https://www.ebi.ac.uk/pdbsum/4f49 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f49 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/R1A_CVPPU R1A_CVPPU]] The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3 (By similarity).  The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SAGC]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK.  Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter (By similarity).  Nsp9 is a ssRNA-binding protein (By similarity).
+[https://www.uniprot.org/uniprot/R1A_CVPPU R1A_CVPPU] The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3 (By similarity).  The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SAGC]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK.  Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter (By similarity).  Nsp9 is a ssRNA-binding protein (By similarity).
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Cvppu]]
+[[Category: Large Structures]]
-[[Category: Alliston, K R]]
+[[Category: Porcine transmissible gastroenteritis coronavirus strain Purdue]]
-[[Category: Battaile, K P]]
+[[Category: Alliston KR]]
-[[Category: Chang, K O]]
+[[Category: Battaile KP]]
-[[Category: Groutas, W C]]
+[[Category: Chang K-O]]
-[[Category: Kim, Y]]
+[[Category: Groutas WC]]
-[[Category: Lovell, S]]
+[[Category: Kim Y]]
-[[Category: Mandadapu, S R]]
+[[Category: Lovell S]]
-[[Category: Tiew, K C]]
+[[Category: Mandadapu SR]]
-[[Category: Antiviral inhibitor]]
+[[Category: Tiew K-C]]
-[[Category: Dipeptidyl inhibitor]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Protease]]

4f49

From Proteopedia

Current revision

2.25A resolution structure of Transmissible Gastroenteritis Virus Protease containing a covalently bound Dipeptidyl Inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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