2yj9: Difference between revisions
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<StructureSection load='2yj9' size='340' side='right' caption='[[2yj9]], [[Resolution|resolution]] 1.35Å' scene=''> | <StructureSection load='2yj9' size='340' side='right' caption='[[2yj9]], [[Resolution|resolution]] 1.35Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2yj9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YJ9 OCA]. <br> | <table><tr><td colspan='2'>[[2yj9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YJ9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YJ9 FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=YJ9:(2S,4R)-4-(2-CHLOROPHENYL)SULFONYL-N-[1-(IMINOMETHYL)CYCLOPROPYL]-1-[1-[4-(TRIFLUOROMETHYL)PHENYL]CYCLOPROPYL]CARBONYL-PYRROLIDINE-2-CARBOXAMIDE'>YJ9</scene>< | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=YJ9:(2S,4R)-4-(2-CHLOROPHENYL)SULFONYL-N-[1-(IMINOMETHYL)CYCLOPROPYL]-1-[1-[4-(TRIFLUOROMETHYL)PHENYL]CYCLOPROPYL]CARBONYL-PYRROLIDINE-2-CARBOXAMIDE'>YJ9</scene></td></tr> | ||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1cjl|1cjl]], [[1cs8|1cs8]], [[2xu4|2xu4]], [[2vhs|2vhs]], [[1icf|1icf]], [[2xu3|2xu3]], [[1mhw|1mhw]], [[2xu5|2xu5]], [[2xu1|2xu1]], [[2yjb|2yjb]], [[2yj8|2yj8]], [[2yj2|2yj2]], [[2yjc|2yjc]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1cjl|1cjl]], [[1cs8|1cs8]], [[2xu4|2xu4]], [[2vhs|2vhs]], [[1icf|1icf]], [[2xu3|2xu3]], [[1mhw|1mhw]], [[2xu5|2xu5]], [[2xu1|2xu1]], [[2yjb|2yjb]], [[2yj8|2yj8]], [[2yj2|2yj2]], [[2yjc|2yjc]]</td></tr> | ||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cathepsin_L Cathepsin L], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.15 3.4.22.15] </span></td></tr> | ||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2yj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yj9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2yj9 RCSB], [http://www.ebi.ac.uk/pdbsum/2yj9 PDBsum]</span></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=2yj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yj9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2yj9 RCSB], [http://www.ebi.ac.uk/pdbsum/2yj9 PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/CATL1_HUMAN CATL1_HUMAN]] Important for the overall degradation of proteins in lysosomes. | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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Halogen Bonding at the Active Sites of Human Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments.,Hardegger LA, Kuhn B, Spinnler B, Anselm L, Ecabert R, Stihle M, Gsell B, Thoma R, Diez J, Benz J, Plancher JM, Hartmann G, Isshiki Y, Morikami K, Shimma N, Haap W, Banner DW, Diederich F ChemMedChem. 2011 Nov 4;6(11):2048-54. doi: 10.1002/cmdc.201100353. Epub, 2011 Sep 6. PMID:21898833<ref>PMID:21898833</ref> | Halogen Bonding at the Active Sites of Human Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments.,Hardegger LA, Kuhn B, Spinnler B, Anselm L, Ecabert R, Stihle M, Gsell B, Thoma R, Diez J, Benz J, Plancher JM, Hartmann G, Isshiki Y, Morikami K, Shimma N, Haap W, Banner DW, Diederich F ChemMedChem. 2011 Nov 4;6(11):2048-54. doi: 10.1002/cmdc.201100353. Epub, 2011 Sep 6. PMID:21898833<ref>PMID:21898833</ref> | ||
From | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
==See Also== | |||
*[[Cathepsin|Cathepsin]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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[[Category: Cathepsin L]] | [[Category: Cathepsin L]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Banner, D W | [[Category: Banner, D W]] | ||
[[Category: Benz, J M | [[Category: Benz, J M]] | ||
[[Category: Haap, W | [[Category: Haap, W]] | ||
[[Category: Drug design]] | [[Category: Drug design]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Thiol protease]] | [[Category: Thiol protease]] | ||
Revision as of 15:40, 25 December 2014
CATHEPSIN L WITH A NITRILE INHIBITORCATHEPSIN L WITH A NITRILE INHIBITOR
Structural highlights
Function[CATL1_HUMAN] Important for the overall degradation of proteins in lysosomes. Publication Abstract from PubMedIn two series of small-molecule ligands, one inhibiting human cathepsin L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X-ray co-crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone CO in the S3 pocket of hcatL and in a back pocket of MEK1. While the S3 pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein-ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (C(aryl) X) and the XB acceptor (CO) in the correct geometry. New X-ray co-crystal structures in the same crystal form (space group P2(1) 2(1) 2(1) ) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high-resolution structures reveal that the backbone CO group of Gly61 in most hcatL co-crystal structures maintains water solvation while engaging in XB. An arylCF(3) -substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF(3) group pointing to the CO group of Gly61 in the S3 pocket. In this case, a repulsive F(2) CFOC contact apparently is energetically overcompensated by other favorable protein-ligand contacts established by the CF(3) group. Halogen Bonding at the Active Sites of Human Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments.,Hardegger LA, Kuhn B, Spinnler B, Anselm L, Ecabert R, Stihle M, Gsell B, Thoma R, Diez J, Benz J, Plancher JM, Hartmann G, Isshiki Y, Morikami K, Shimma N, Haap W, Banner DW, Diederich F ChemMedChem. 2011 Nov 4;6(11):2048-54. doi: 10.1002/cmdc.201100353. Epub, 2011 Sep 6. PMID:21898833[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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