6y7m
From Proteopedia
(Difference between revisions)
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<StructureSection load='6y7m' size='340' side='right'caption='[[6y7m]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='6y7m' size='340' side='right'caption='[[6y7m]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6y7m]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y7M OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6y7m]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hcov-sars Hcov-sars]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y7M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Y7M FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=OEW:~{tert}-butyl+~{N}-[1-[(2~{S})-3-cyclohexyl-1-[[(2~{S},3~{R})-4-(cyclopropylamino)-3-oxidanyl-4-oxidanylidene-1-[(3~{R})-2-oxidanylidene-3,4-dihydropyrrol-3-yl]butan-2-yl]amino]-1-oxidanylidene-propan-2-yl]-2-oxidanylidene-pyridin-3-yl]carbamate'>OEW</scene></td></tr> | + | </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=OEW:~{tert}-butyl+~{N}-[1-[(2~{S})-3-cyclohexyl-1-[[(2~{S},3~{R})-4-(cyclopropylamino)-3-oxidanyl-4-oxidanylidene-1-[(3~{R})-2-oxidanylidene-3,4-dihydropyrrol-3-yl]butan-2-yl]amino]-1-oxidanylidene-propan-2-yl]-2-oxidanylidene-pyridin-3-yl]carbamate'>OEW</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">1a ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=694009 HCoV-SARS])</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=6y7m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y7m OCA], [https://pdbe.org/6y7m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6y7m RCSB], [https://www.ebi.ac.uk/pdbsum/6y7m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6y7m ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
| - | [[ | + | [[https://www.uniprot.org/uniprot/R1A_CVHSA R1A_CVHSA]] The papain-like proteinase (PL-PRO) is responsible for the cleavages located at the N-terminus of replicase polyprotein. In addition, PL-PRO 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.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> 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 (By similarity). Also contains an ADP-ribose-1''-phosphate (ADRP)-binding function.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> Nsp9 is a ssRNA-binding protein.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. An attractive drug target among coronaviruses is the main protease (M(pro), 3CL(pro)), due to its essential role in processing the polyproteins that are translated from the viral RNA. We report the X-ray structures of the unliganded SARS-CoV-2 M(pro) and its complex with an alpha-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. Based on the structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M(pro) The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route. | ||
| + | |||
| + | Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors.,Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R Science. 2020 Mar 20. pii: science.abb3405. doi: 10.1126/science.abb3405. PMID:32198291<ref>PMID:32198291</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6y7m" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Hcov-sars]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hilgenfeld, R]] | [[Category: Hilgenfeld, R]] | ||
Revision as of 10:44, 31 March 2021
Crystal structure of the complex resulting from the reaction between the SARS-CoV main protease and tert-butyl (1-((S)-3-cyclohexyl-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate
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