View source for 2nqg


==Calpain 1 proteolytic core inactivated by WR18(S,S), an epoxysuccinyl-type inhibitor.==
<StructureSection load='2nqg' size='340' side='right'caption='[[2nqg]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2nqg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NQG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NQG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.04&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NQG:5-AZANYLIDYNE-N-[(2S)-4-ETHOXY-2-HYDROXY-4-OXOBUTANOYL]-L-NORVALYL-L-ARGINYL-L-TRYPTOPHANAMIDE'>NQG</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=2nqg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nqg OCA], [https://pdbe.org/2nqg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2nqg RCSB], [https://www.ebi.ac.uk/pdbsum/2nqg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2nqg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CAN1_RAT CAN1_RAT] Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.
== 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/nq/2nqg_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2nqg ConSurf].
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== Publication Abstract from PubMed ==
Calpains are calcium-dependent proteases that are required for numerous intracellular processes but also play an important role in the development of pathologies such as ischemic injury and neurodegeneration. Many current small molecule calpain inhibitors also inhibit other cysteine proteases, including cathepsins, and need improved selectivity. The specificity of inhibition of several calpains and papain was profiled using synthetic positional scanning libraries of epoxide-based compounds that target the active-site cysteine. These peptidomimetic libraries probe the P4, P3, and P2 positions, display (S,S)- or (R,R)-epoxide stereochemistries, and incorporate both natural and non-natural amino acids. To facilitate library screening, an SDS-PAGE assay that measures the extent of hydrolysis of an inactive recombinant m-calpain was developed. Individual epoxide inhibitors were synthesized guided by calpain-specific preferences observed from the profiles and tested for inhibition against calpain. The most potent compounds were assayed for specificity against cathepsins B, L, and K. Several compounds demonstrated high inhibition specificity for calpains over cathepsins. The best of these inhibitors, WRH(R,R), irreversibly inactivates m- and mu-calpain rapidly (k(2)/K(i) = 131,000 and 16,500 m(-1) s(-1), respectively) but behaves exclusively as a reversible and less potent inhibitor toward the cathepsins. X-ray crystallography of the proteolytic core of rat mu-calpain inactivated by the epoxide compounds WR gamma-cyano-alpha-aminobutyric acid (S,S) and WR allylglycine (R,R) reveals that the stereochemistry of the epoxide influences positioning and orientation of the P2 residue, facilitating alternate interactions within the S2 pocket. Moreover, the WR gamma-cyano-alpha-aminobutyric acid (S,S)-complexed structure defines a novel hydrogen-bonding site within the S2 pocket of calpains.

Development of calpain-specific inactivators by screening of positional scanning epoxide libraries.,Cuerrier D, Moldoveanu T, Campbell RL, Kelly J, Yoruk B, Verhelst SH, Greenbaum D, Bogyo M, Davies PL J Biol Chem. 2007 Mar 30;282(13):9600-11. Epub 2007 Jan 11. PMID:17218315<ref>PMID:17218315</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2nqg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Calpain 3D structures|Calpain 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Campbell RL]]
[[Category: Cuerrier D]]
[[Category: Davies PL]]
[[Category: Moldoveanu T]]