3mj5: Difference between revisions

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{{STRUCTURE_3mj5|  PDB=3mj5  |  SCENE=  }}
==Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation==
===Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation===
<StructureSection load='3mj5' size='340' side='right' caption='[[3mj5]], [[Resolution|resolution]] 2.63&Aring;' scene=''>
{{ABSTRACT_PUBMED_20527968}}
== Structural highlights ==
<table><tr><td colspan='2'>[[3mj5]] is a 2 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=3MJ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MJ5 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GRM:N-(1,3-BENZODIOXOL-5-YLMETHYL)-1-[(1R)-1-NAPHTHALEN-1-YLETHYL]PIPERIDINE-4-CARBOXAMIDE'>GRM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2fe8|2fe8]], [[3e9s|3e9s]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">1a, ORF1 (nsp3) residues 1544-1855 ([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=3mj5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mj5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mj5 RCSB], [http://www.ebi.ac.uk/pdbsum/3mj5 PDBsum]</span></td></tr>
</table>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mj/3mj5_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC(50) = 0.56 muM; antiviral EC(50) = 9.1 muM) and the corresponding (R)-Me 15g (IC(50) = 0.32 muM; antiviral EC(50) = 9.1 muM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.


==Function==
Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation.,Ghosh AK, Takayama J, Rao KV, Ratia K, Chaudhuri R, Mulhearn DC, Lee H, Nichols DB, Baliji S, Baker SC, Johnson ME, Mesecar AD J Med Chem. 2010 Jun 9. PMID:20527968<ref>PMID:20527968</ref>
[[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>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3mj5]] is a 2 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=3MJ5 OCA].
</div>
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:020527968</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Sars coronavirus]]
[[Category: Sars coronavirus]]
[[Category: Mesecar, A D.]]
[[Category: Mesecar, A D]]
[[Category: Pegan, S D.]]
[[Category: Pegan, S D]]
[[Category: Ratia, K M.]]
[[Category: Ratia, K M]]
[[Category: Cysteine protease]]
[[Category: Cysteine protease]]
[[Category: Non-covalent inhibitor]]
[[Category: Non-covalent inhibitor]]
[[Category: Sars coronavirus]]
[[Category: Viral protein]]
[[Category: Viral protein]]
[[Category: Zinc-finger]]
[[Category: Zinc-finger]]

Revision as of 20:54, 18 December 2014

Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological EvaluationSevere Acute Respiratory Syndrome-Coronavirus Papain-Like Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation

Structural highlights

3mj5 is a 2 chain structure with sequence from Sars coronavirus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:1a, ORF1 (nsp3) residues 1544-1855 (SARS coronavirus)
Resources:FirstGlance, OCA, RCSB, PDBsum

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 design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC(50) = 0.56 muM; antiviral EC(50) = 9.1 muM) and the corresponding (R)-Me 15g (IC(50) = 0.32 muM; antiviral EC(50) = 9.1 muM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.

Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation.,Ghosh AK, Takayama J, Rao KV, Ratia K, Chaudhuri R, Mulhearn DC, Lee H, Nichols DB, Baliji S, Baker SC, Johnson ME, Mesecar AD J Med Chem. 2010 Jun 9. PMID:20527968[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Ghosh AK, Takayama J, Rao KV, Ratia K, Chaudhuri R, Mulhearn DC, Lee H, Nichols DB, Baliji S, Baker SC, Johnson ME, Mesecar AD. Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation. J Med Chem. 2010 Jun 9. PMID:20527968 doi:10.1021/jm1004489

3mj5, resolution 2.63Å

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