1kyn
From Proteopedia
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| , resolution 3.50Å | |||||||
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| Sites: | and | ||||||
| Ligands: | |||||||
| Activity: | Cathepsin G, with EC number 3.4.21.20 | ||||||
| Domains: | Tryp_SPc | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Cathepsin-G
Overview
The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 A). Structural details from the X-ray analysis of 1.Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.
About this Structure
1KYN is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design., Greco MN, Hawkins MJ, Powell ET, Almond HR Jr, Corcoran TW, de Garavilla L, Kauffman JA, Recacha R, Chattopadhyay D, Andrade-Gordon P, Maryanoff BE, J Am Chem Soc. 2002 Apr 17;124(15):3810-1. PMID:11942800
Page seeded by OCA on Wed Apr 2 11:31:27 2008
