View source for 3d62


==Development of Broad-Spectrum Halomethyl Ketone Inhibitors Against Coronavirus Main Protease 3CLpro==
<StructureSection load='3d62' size='340' side='right'caption='[[3d62]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3d62]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Cvhsa Cvhsa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D62 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D62 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=959:BENZYL+(2-OXOPROPYL)CARBAMATE'>959</scene></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=227859 CVHSA])</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=3d62 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d62 OCA], [https://pdbe.org/3d62 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d62 RCSB], [https://www.ebi.ac.uk/pdbsum/3d62 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d62 ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/R1AB_CVHSA R1AB_CVHSA]] 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 (By similarity).<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>   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>   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). Activity of helicase is dependent on magnesium.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>   The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction.<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>   NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>  
== 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/d6/3d62_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/main_output.php?pdb_ID=3d62 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Coronaviruses comprise a large group of RNA viruses with diverse host specificity. The emergence of highly pathogenic strains like the SARS coronavirus (SARS-CoV), and the discovery of two new coronaviruses, NL-63 and HKU1, corroborates the high rate of mutation and recombination that have enabled them to cross species barriers and infect novel hosts. For that reason, the development of broad-spectrum antivirals that are effective against several members of this family is highly desirable. This goal can be accomplished by designing inhibitors against a target, such as the main protease 3CL(pro) (M(pro)), which is highly conserved among all coronaviruses. Here 3CL(pro) derived from the SARS-CoV was used as the primary target to identify a new class of inhibitors containing a halomethyl ketone warhead. The compounds are highly potent against SARS 3CL(pro) with K(i)'s as low as 300 nM. The crystal structure of the complex of one of the compounds with 3CL(pro) indicates that this inhibitor forms a thioether linkage between the halomethyl carbon of the warhead and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR) studies of these compounds have led to the identification of a pharmacophore that accurately defines the essential molecular features required for the high affinity.

Development of broad-spectrum halomethyl ketone inhibitors against coronavirus main protease 3CL(pro).,Bacha U, Barrila J, Gabelli SB, Kiso Y, Mario Amzel L, Freire E Chem Biol Drug Des. 2008 Jul;72(1):34-49. PMID:18611220<ref>PMID:18611220</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3d62" style="background-color:#fffaf0;"></div>

==See Also==
*[[Virus protease 3D structures|Virus protease 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Cvhsa]]
[[Category: Large Structures]]
[[Category: Amzel, L M]]
[[Category: Bacha, U]]
[[Category: Barrila, J]]
[[Category: Freire, E]]
[[Category: Gabelli, S B]]
[[Category: Kiso, Y]]
[[Category: Atp-binding]]
[[Category: Endonuclease]]
[[Category: Exonuclease]]
[[Category: Helicase]]
[[Category: Hydrolase]]
[[Category: Inhibitor]]
[[Category: Main protease 3clpro]]
[[Category: Membrane]]
[[Category: Metal-binding]]
[[Category: Nuclease]]
[[Category: Nucleotide-binding]]
[[Category: Nucleotidyltransferase]]
[[Category: Rna replication]]
[[Category: Rna-binding]]
[[Category: Rna-directed rna polymerase]]
[[Category: Sar]]
[[Category: Thiol protease]]
[[Category: Transferase]]
[[Category: Transmembrane]]
[[Category: Zinc-finger]]