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| | <StructureSection load='5gwz' size='340' side='right'caption='[[5gwz]], [[Resolution|resolution]] 2.44Å' scene=''> | | <StructureSection load='5gwz' size='340' side='right'caption='[[5gwz]], [[Resolution|resolution]] 2.44Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5gwz]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Pedv Pedv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5GWZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GWZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5gwz]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Porcine_epidemic_diarrhea_virus_CV777 Porcine epidemic diarrhea virus CV777] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5GWZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5GWZ FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=010:PHENYLMETHANOL'>010</scene>, <scene name='pdbligand=02J:5-METHYL-1,2-OXAZOLE-3-CARBOXYLIC+ACID'>02J</scene>, <scene name='pdbligand=PJE:(E,4S)-4-AZANYL-5-[(3S)-2-OXIDANYLIDENEPYRROLIDIN-3-YL]PENT-2-ENOIC+ACID'>PJE</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]] 2.444Å</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=229032 PEDV])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=010:PHENYLMETHANOL'>010</scene>, <scene name='pdbligand=02J:5-METHYL-1,2-OXAZOLE-3-CARBOXYLIC+ACID'>02J</scene>, <scene name='pdbligand=PJE:(E,4S)-4-AZANYL-5-[(3S)-2-OXIDANYLIDENEPYRROLIDIN-3-YL]PENT-2-ENOIC+ACID'>PJE</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=5gwz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gwz OCA], [http://pdbe.org/5gwz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gwz RCSB], [http://www.ebi.ac.uk/pdbsum/5gwz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gwz 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=5gwz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gwz OCA], [https://pdbe.org/5gwz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5gwz RCSB], [https://www.ebi.ac.uk/pdbsum/5gwz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5gwz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/R1A_PEDV7 R1A_PEDV7]] 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-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK. Also contains an ADP-ribose-1''-phosphate (ADRP)-binding function (By similarity).[PROSITE-ProRule:PRU00772] Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter. Nsp9 is a ssRNA-binding protein. | + | [https://www.uniprot.org/uniprot/R1A_PEDV7 R1A_PEDV7] 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-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK. Also contains an ADP-ribose-1''-phosphate (ADRP)-binding function (By similarity).[PROSITE-ProRule:PRU00772] Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter. Nsp9 is a ssRNA-binding protein. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pedv]] | + | [[Category: Porcine epidemic diarrhea virus CV777]] |
| - | [[Category: Cai, Y]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Chen, C]] | + | [[Category: Cai Y]] |
| - | [[Category: Chen, X]] | + | [[Category: Chen C]] |
| - | [[Category: Liu, H]] | + | [[Category: Chen X]] |
| - | [[Category: Liu, X]] | + | [[Category: Liu H]] |
| - | [[Category: Wang, F]] | + | [[Category: Liu X]] |
| - | [[Category: Xu, Y]] | + | [[Category: Wang F]] |
| - | [[Category: Yang, H]] | + | [[Category: Xu Y]] |
| - | [[Category: Yang, K]] | + | [[Category: Yang H]] |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | [[Category: Yang K]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Main protease]]
| + | |
| Structural highlights
Function
R1A_PEDV7 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-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK. Also contains an ADP-ribose-1-phosphate (ADRP)-binding function (By similarity).[PROSITE-ProRule:PRU00772] Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter. Nsp9 is a ssRNA-binding protein.
Publication Abstract from PubMed
Porcine epidemic diarrhea virus (PEDV) causes high mortality in pigs. PEDV main protease (Mpro) plays an essential role in viral replication. We solved the structure of PEDV Mpro complexed with peptidomimetic inhibitor N3 carrying a Michael acceptor warhead, revealing atomic level interactions. We further designed a series of 17 inhibitors with altered side groups. Inhibitors M2 and M17 demonstrated enhanced specificity against PEDV Mpro. These compounds have potential as future therapeutics to combat PEDV infection.
Michael Acceptor-Based Peptidomimetic Inhibitor of Main Protease from Porcine Epidemic Diarrhea Virus.,Wang F, Chen C, Yang K, Xu Y, Liu X, Gao F, Liu H, Chen X, Zhao Q, Liu X, Cai Y, Yang H J Med Chem. 2017 Mar 28. doi: 10.1021/acs.jmedchem.7b00103. PMID:28287727[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang F, Chen C, Yang K, Xu Y, Liu X, Gao F, Liu H, Chen X, Zhao Q, Liu X, Cai Y, Yang H. Michael Acceptor-Based Peptidomimetic Inhibitor of Main Protease from Porcine Epidemic Diarrhea Virus. J Med Chem. 2017 Mar 28. doi: 10.1021/acs.jmedchem.7b00103. PMID:28287727 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00103
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