3v3m
From Proteopedia
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| - | [[ | + | ==Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease in Complex with N-[(1R)-2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-N-(4-tert-butylphenyl)furan-2-carboxamide inhibitor.== |
| + | <StructureSection load='3v3m' size='340' side='right' caption='[[3v3m]], [[Resolution|resolution]] 1.96Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[3v3m]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Sars_coronavirus Sars coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V3M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3V3M FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EN:N-[(1R)-2-(TERT-BUTYLAMINO)-2-OXO-1-(PYRIDIN-3-YL)ETHYL]-N-(4-TERT-BUTYLPHENYL)FURAN-2-CARBOXAMIDE'>0EN</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></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=227859 SARS coronavirus])</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=3v3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v3m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3v3m RCSB], [http://www.ebi.ac.uk/pdbsum/3v3m PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://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 == | ||
| + | A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)f uran-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action. | ||
| - | + | Discovery, Synthesis, And Structure-Based Optimization of a Series of N-(tert-Butyl)-2-(N-arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease.,Jacobs J, Grum-Tokars V, Zhou Y, Turlington M, Saldanha SA, Chase P, Eggler A, Dawson ES, Baez-Santos YM, Tomar S, Mielech AM, Baker SC, Lindsley CW, Hodder P, Mesecar A, Stauffer SR J Med Chem. 2013 Jan 3. PMID:23231439<ref>PMID:23231439</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | + | <references/> | |
| - | == | + | __TOC__ |
| - | + | </StructureSection> | |
[[Category: Sars coronavirus]] | [[Category: Sars coronavirus]] | ||
| - | [[Category: Baez-Santos, Y M | + | [[Category: Baez-Santos, Y M]] |
| - | [[Category: Baker, S C | + | [[Category: Baker, S C]] |
| - | [[Category: Chase, P | + | [[Category: Chase, P]] |
| - | [[Category: Dawson, E S | + | [[Category: Dawson, E S]] |
| - | [[Category: Eggler, A | + | [[Category: Eggler, A]] |
| - | [[Category: Grum-Tokars, V | + | [[Category: Grum-Tokars, V]] |
| - | [[Category: Hodder, P | + | [[Category: Hodder, P]] |
| - | [[Category: Jacobs, J | + | [[Category: Jacobs, J]] |
| - | [[Category: Lindsley, C W | + | [[Category: Lindsley, C W]] |
| - | [[Category: Mesecar, A | + | [[Category: Mesecar, A]] |
| - | [[Category: Mielech, A M | + | [[Category: Mielech, A M]] |
| - | [[Category: Saldanha, S A | + | [[Category: Saldanha, S A]] |
| - | [[Category: Stauffer, S R | + | [[Category: Stauffer, S R]] |
| - | [[Category: Tomar, S | + | [[Category: Tomar, S]] |
| - | [[Category: Turlington, M | + | [[Category: Turlington, M]] |
| - | [[Category: Zhou, Y | + | [[Category: Zhou, Y]] |
[[Category: Chymotrypsin like fold]] | [[Category: Chymotrypsin like fold]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Viral polypeptide protease]] | [[Category: Viral polypeptide protease]] | ||
Revision as of 16:34, 25 December 2014
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease in Complex with N-[(1R)-2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-N-(4-tert-butylphenyl)furan-2-carboxamide inhibitor.
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Categories: Sars coronavirus | Baez-Santos, Y M | Baker, S C | Chase, P | Dawson, E S | Eggler, A | Grum-Tokars, V | Hodder, P | Jacobs, J | Lindsley, C W | Mesecar, A | Mielech, A M | Saldanha, S A | Stauffer, S R | Tomar, S | Turlington, M | Zhou, Y | Chymotrypsin like fold | Hydrolase | Hydrolase-hydrolase inhibitor complex | Viral polypeptide protease
