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| | <StructureSection load='3d23' size='340' side='right'caption='[[3d23]], [[Resolution|resolution]] 2.50Å' scene=''> | | <StructureSection load='3d23' size='340' side='right'caption='[[3d23]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3d23]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Cvhn1 Cvhn1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D23 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D23 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3d23]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_coronavirus_HKU1_(isolate_N1) Human coronavirus HKU1 (isolate N1)] 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=3D23 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D23 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]] 2.5Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">rep ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=443239 CVHN1])</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'>[https://proteopedia.org/fgij/fg.htm?mol=3d23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d23 OCA], [https://pdbe.org/3d23 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d23 RCSB], [https://www.ebi.ac.uk/pdbsum/3d23 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d23 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=3d23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d23 OCA], [https://pdbe.org/3d23 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d23 RCSB], [https://www.ebi.ac.uk/pdbsum/3d23 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d23 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/R1AB_CVHN1 R1AB_CVHN1]] The replicase polyprotein of coronaviruses is a multifunctional protein: it contains the activities necessary for the transcription of negative stranded RNA, leader RNA, subgenomic mRNAs and progeny virion RNA as well as proteinases responsible for the cleavage of the polyprotein into functional products. The papain-like proteinase 1 (PL1-PRO) and papain-like proteinase 2 (PL2-PRO) 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. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent 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). The helicase which contains a zinc finger structure displays RNA and DNA duplex-unwinding activities with 5' to 3' polarity. ATPase activity is strongly stimulated by poly(U), poly(dT), poly(C), poly(dA), but not by poly(G) (By similarity). The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction (By similarity). 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). NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond (By similarity).
| + | [https://www.uniprot.org/uniprot/R1A_CVHN1 R1A_CVHN1] The papain-like proteinase 1 (PL1-PRO) and papain-like proteinase 2 (PL2-PRO) 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. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF-3 (By similarity). 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. Catalytic subunit of viral RNA capping enzyme which catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs. The kinase-like NiRAN domain of NSP12 transfers RNA to the amino terminus of NSP9, forming a covalent RNA-protein intermediate. Subsequently, the NiRAN domain transfers RNA to GDP, forming the core cap structure GpppA-RNA. The NSP14 and NSP16 methyltransferases then add methyl groups to form functional cap structures.[UniProtKB:P0DTC1] Binds to the 40S ribosomal subunit and inhibits host translation. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response (By similarity). |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cvhn1]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chen, C]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Li, S]] | + | [[Category: Chen C]] |
| - | [[Category: Zhao, Q]] | + | [[Category: Li S]] |
| - | [[Category: Zou, Y]] | + | [[Category: Zhao Q]] |
| - | [[Category: Atp-binding]]
| + | [[Category: Zou Y]] |
| - | [[Category: Endonuclease]]
| + | |
| - | [[Category: Exonuclease]]
| + | |
| - | [[Category: Helicase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Main protease]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Nuclease]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Nucleotidyltransferase]]
| + | |
| - | [[Category: Protease]]
| + | |
| - | [[Category: Rna replication]]
| + | |
| - | [[Category: Rna-binding]]
| + | |
| - | [[Category: Rna-directed rna polymerase]]
| + | |
| - | [[Category: Thiol protease]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| - | [[Category: Zinc-finger]]
| + | |
| Structural highlights
Function
R1A_CVHN1 The papain-like proteinase 1 (PL1-PRO) and papain-like proteinase 2 (PL2-PRO) 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. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF-3 (By similarity). 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. Catalytic subunit of viral RNA capping enzyme which catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs. The kinase-like NiRAN domain of NSP12 transfers RNA to the amino terminus of NSP9, forming a covalent RNA-protein intermediate. Subsequently, the NiRAN domain transfers RNA to GDP, forming the core cap structure GpppA-RNA. The NSP14 and NSP16 methyltransferases then add methyl groups to form functional cap structures.[UniProtKB:P0DTC1] Binds to the 40S ribosomal subunit and inhibits host translation. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response (By similarity).
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The newly emergent human coronavirus HKU1 (HCoV-HKU1) was first identified in Hong Kong in 2005. Infection by HCoV-HKU1 occurs worldwide and causes syndromes such as the common cold, bronchitis, and pneumonia. The CoV main protease (M(pro)), which is a key enzyme in viral replication via the proteolytic processing of the replicase polyproteins, has been recognized as an attractive target for rational drug design. In this study, we report the structure of HCoV-HKU1 M(pro) in complex with a Michael acceptor, inhibitor N3. The structure of HCoV-HKU1 provides a high-quality model for group 2A CoVs, which are distinct from group 2B CoVs such as severe acute respiratory syndrome CoV. The structure, together with activity assays, supports the relative conservation at the P1 position that was discovered by sequencing the HCoV-HKU1 genome. Combined with structural data from other CoV M(pro)s, the HCoV-HKU1 M(pro) structure reported here provides insights into both substrate preference and the design of antivirals targeting CoVs.
Structure of the main protease from a global infectious human coronavirus, HCoV-HKU1.,Zhao Q, Li S, Xue F, Zou Y, Chen C, Bartlam M, Rao Z J Virol. 2008 Sep;82(17):8647-55. Epub 2008 Jun 18. PMID:18562531[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhao Q, Li S, Xue F, Zou Y, Chen C, Bartlam M, Rao Z. Structure of the main protease from a global infectious human coronavirus, HCoV-HKU1. J Virol. 2008 Sep;82(17):8647-55. Epub 2008 Jun 18. PMID:18562531 doi:10.1128/JVI.00298-08
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