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==A combined crystallographic and molecular dynamics study of cathepsin-L retro-binding inhibitors(compound 4)== | |||
<StructureSection load='3h89' size='340' side='right'caption='[[3h89]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3h89]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H89 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H89 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NSX:N~2~,N~6~-BIS(BIPHENYL-4-YLACETYL)-L-LYSYL-D-ARGINYL-N-(2-PHENYLETHYL)-L-TYROSINAMIDE'>NSX</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3h8b|3h8b]], [[3h8c|3h8c]]</div></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Catehpsin L ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Cathepsin_L Cathepsin L], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.15 3.4.22.15] </span></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=3h89 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h89 OCA], [https://pdbe.org/3h89 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h89 RCSB], [https://www.ebi.ac.uk/pdbsum/3h89 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h89 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/CATL1_HUMAN CATL1_HUMAN]] Important for the overall degradation of proteins in lysosomes. | |||
== 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/h8/3h89_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=3h89 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We report the crystal structures of three noncovalent retrobinding inhibitors in complex with mature cathepsin L up to resolutions of 2.5, 1.8, and 2.5 A, respectively. These inhibitors were Bpa-(Nepsilon-Bpa)Lys-DArg-Tyr-Npe, Bpa-(Nepsilon-Bpa)Lys-DArg-Phe-Npe, and Bpa-MCys-DArg-Phe-Npe, where Bpa = biphenylacetyl and Pea = N-phenylethyl. These were selected to clarify the binding mode of the biphenyl groups in the S' subsites because the addition of a second biphenyl does not improve potency. Examination of the symmetry-related monomers in the crystal structures revealed inhibitor-inhibitor crystal packing interactions. Molecular dynamics simulations were then used to explore the structure and dynamical behavior of the isolated protein-ligand complexes in solution. In the simulations, the backbone biphenyl groups for all three inhibitors ended up in the same location despite having started out in different orientations in the initial crystal structure conformations. The lack of improved potency of the larger inhibitors over the smaller one is attributed to a correspondingly greater entropic cost of binding. | |||
A combined crystallographic and molecular dynamics study of cathepsin L retrobinding inhibitors.,Shenoy RT, Chowdhury SF, Kumar S, Joseph L, Purisima EO, Sivaraman J J Med Chem. 2009 Oct 22;52(20):6335-46. PMID:19761244<ref>PMID:19761244</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3h89" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cathepsin 3D structures|Cathepsin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Cathepsin L]] | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Chowdhury, S F]] | |||
[[Category: Joseph, L]] | |||
[[Category: Kumar, S]] | |||
[[Category: Purisima, E O]] | |||
[[Category: Sivaraman, J]] | |||
[[Category: Tulsidas, S R]] | |||
[[Category: Cathepsin l]] | |||
[[Category: Cysteine protease]] | |||
[[Category: Disulfide bond]] | |||
[[Category: Glycoprotein]] | |||
[[Category: Hydrolase]] | |||
[[Category: Lysosome]] | |||
[[Category: Protease]] | |||
[[Category: Thiol protease]] | |||
[[Category: Zymogen]] | |||