2h7j
From Proteopedia
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|PDB= 2h7j |SIZE=350|CAPTION= <scene name='initialview01'>2h7j</scene>, resolution 1.50Å | |PDB= 2h7j |SIZE=350|CAPTION= <scene name='initialview01'>2h7j</scene>, resolution 1.50Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=H7J:N-[(1S)-1-{1-[(1R,3E)-1-ACETYLPENT-3-EN-1-YL]-1H-1,2,3-TRIAZOL-4-YL}-1,2-DIMETHYLPROPYL]BENZAMIDE'>H7J</scene> | + | |LIGAND= <scene name='pdbligand=H7J:N-[(1S)-1-{1-[(1R,3E)-1-ACETYLPENT-3-EN-1-YL]-1H-1,2,3-TRIAZOL-4-YL}-1,2-DIMETHYLPROPYL]BENZAMIDE'>H7J</scene>, <scene name='pdbligand=P15:2,5,8,11,14,17-HEXAOXANONADECAN-19-OL'>P15</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Cathepsin_S Cathepsin S], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.27 3.4.22.27] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Cathepsin_S Cathepsin S], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.27 3.4.22.27] </span> |
|GENE= CTSS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= CTSS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2f1g|2F1G]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2h7j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h7j OCA], [http://www.ebi.ac.uk/pdbsum/2h7j PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2h7j RCSB]</span> | ||
}} | }} | ||
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[[Category: Spraggon, G.]] | [[Category: Spraggon, G.]] | ||
[[Category: Wood, W J.]] | [[Category: Wood, W J.]] | ||
| - | [[Category: H7J]] | ||
| - | [[Category: P15]] | ||
[[Category: cathepsin s]] | [[Category: cathepsin s]] | ||
[[Category: chloromethylketone]] | [[Category: chloromethylketone]] | ||
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[[Category: substrate activity screening]] | [[Category: substrate activity screening]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:26:35 2008'' |
Revision as of 00:26, 31 March 2008
| |||||||
| , resolution 1.50Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Gene: | CTSS (Homo sapiens) | ||||||
| Activity: | Cathepsin S, with EC number 3.4.22.27 | ||||||
| Related: | 2F1G
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor.
Overview
The substrate activity screening method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain low nanomolar 1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolically labile aldehyde pharmacophore with the nitrile pharmacophore provided inhibitors with moderate potency for cathepsin S. The inhibitors showed good selectivity over cathepsins B and L but no selectivity over cathepsin K. X-ray structures of two crystal forms (1.5 and 1.9 A) of a complex between cathepsin S and a triazole inhibitor incorporating a chloromethyl ketone pharmacophore guided the design of triazole substrates with increased cleavage efficiency and selectivity for cathepsin S over cathepsins B, L, and K. Conversion of select substrates to nitrile inhibitors yielded a low molecular weight (414 Da) and potent (15 nM) cathepsin S inhibitor that showed >1000-fold selectivity over cathepsins B, L, and K.
About this Structure
2H7J is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Identification of selective, nonpeptidic nitrile inhibitors of cathepsin s using the substrate activity screening method., Patterson AW, Wood WJ, Hornsby M, Lesley S, Spraggon G, Ellman JA, J Med Chem. 2006 Oct 19;49(21):6298-307. PMID:17034136
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