6fv1

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<StructureSection load='6fv1' size='340' side='right'caption='[[6fv1]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
<StructureSection load='6fv1' size='340' side='right'caption='[[6fv1]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6fv1]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Cvhnl Cvhnl]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FV1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FV1 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6fv1]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_coronavirus_NL63 Human coronavirus NL63]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FV1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FV1 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=E8E:(2~{S})-4-methyl-~{N}-[(2~{S},3~{R})-3-oxidanyl-4-oxidanylidene-1-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]-4-[(phenylmethyl)amino]butan-2-yl]-2-[[(~{E})-3-phenylprop-2-enoyl]amino]pentanamide'>E8E</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">rep, 1a-1b ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=277944 CVHNL])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=E8E:(2~{S})-4-methyl-~{N}-[(2~{S},3~{R})-3-oxidanyl-4-oxidanylidene-1-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]-4-[(phenylmethyl)amino]butan-2-yl]-2-[[(~{E})-3-phenylprop-2-enoyl]amino]pentanamide'>E8E</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6fv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fv1 OCA], [https://pdbe.org/6fv1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fv1 RCSB], [https://www.ebi.ac.uk/pdbsum/6fv1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fv1 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=6fv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fv1 OCA], [https://pdbe.org/6fv1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fv1 RCSB], [https://www.ebi.ac.uk/pdbsum/6fv1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fv1 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/R1AB_CVHNL R1AB_CVHNL]] 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.<ref>PMID:20181693</ref> 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] The helicase which contains a zinc finger structure displays RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Its ATPase activity is strongly stimulated by poly(U), poly(dT), poly(C), poly(dA), but not by poly(G).<ref>PMID:20181693</ref> The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction. 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. NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.
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[https://www.uniprot.org/uniprot/R1AB_CVHNL R1AB_CVHNL] 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.<ref>PMID:20181693</ref> 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] The helicase which contains a zinc finger structure displays RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Its ATPase activity is strongly stimulated by poly(U), poly(dT), poly(C), poly(dA), but not by poly(G).<ref>PMID:20181693</ref> The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction. 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. NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic alpha-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the alpha-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.
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alpha-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment.,Zhang L, Lin D, Kusov Y, Nian Y, Ma Q, Wang J, von Brunn A, Leyssen P, Lanko K, Neyts J, de Wilde A, Snijder EJ, Liu H, Hilgenfeld R J Med Chem. 2020 Feb 24. doi: 10.1021/acs.jmedchem.9b01828. PMID:32045235<ref>PMID:32045235</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6fv1" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Cvhnl]]
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[[Category: Human coronavirus NL63]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Hilgenfeld, R]]
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[[Category: Hilgenfeld R]]
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[[Category: Zhang, L]]
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[[Category: Zhang L]]
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[[Category: Alpha-ketoamide]]
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[[Category: Coronavirus]]
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[[Category: Hydrolase]]
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[[Category: Inhibitor]]
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[[Category: Viral protease]]
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Revision as of 07:33, 1 May 2024

Structure of human coronavirus NL63 main protease in complex with the alpha-ketoamide (S)-N-((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-2-cinnamamido-4-methylpentanamide (cinnamoyl-leucine-GlnLactam-CO-CO-NH-benzyl)

PDB ID 6fv1

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