| Structural highlights
Function
[CATG_HUMAN] Serine protease with trypsin- and chymotrypsin-like specificity. Cleaves complement C3. Has antibacterial activity against the Gram-negative bacterium P.aeruginosa, antibacterial activity is inhibited by LPS from P.aeruginosa, Z-Gly-Leu-Phe-CH2Cl and phenylmethylsulfonyl fluoride.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Certain leukocytes release serine proteases that sustain inflammatory processes and cause disease conditions, such as asthma and chronic obstructive pulmonary disease. We identified beta-ketophosphonate 1 (JNJ-10311795; RWJ-355871) as a novel, potent dual inhibitor of neutrophil cathepsin G (K(i) = 38 nm) and mast cell chymase (K(i) = 2.3 nm). The x-ray crystal structures of 1 complexed with human cathepsin G (1.85 A) and human chymase (1.90 A) reveal the molecular basis of the dual inhibition. Ligand 1 occupies the S(1) and S(2) subsites of cathepsin G and chymase similarly, with the 2-naphthyl in S(1), the 1-naphthyl in S(2), and the phosphonate group in a complex network of hydrogen bonds. Surprisingly, however, the carboxamido-N-(naphthalene-2-carboxyl)piperidine group is found to bind in two distinct conformations. In cathepsin G, this group occupies the hydrophobic S(3)/S(4) subsites, whereas in chymase, it does not; rather, it folds onto the 1-naphthyl group of the inhibitor itself. Compound 1 exhibited noteworthy anti-inflammatory activity in rats for glycogen-induced peritonitis and lipopolysaccharide-induced airway inflammation. In addition to a marked reduction in neutrophil influx, 1 reversed increases in inflammatory mediators interleukin-1alpha, interleukin-1beta, tissue necrosis factor-alpha, and monocyte chemotactic protein-1 in the glycogen model and reversed increases in airway nitric oxide levels in the lipopolysaccharide model. These findings demonstrate that it is possible to inhibit both cathepsin G and chymase with a single molecule and suggest an exciting opportunity in the treatment of asthma and chronic obstructive pulmonary disease.
A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo.,de Garavilla L, Greco MN, Sukumar N, Chen ZW, Pineda AO, Mathews FS, Di Cera E, Giardino EC, Wells GI, Haertlein BJ, Kauffman JA, Corcoran TW, Derian CK, Eckardt AJ, Damiano BP, Andrade-Gordon P, Maryanoff BE J Biol Chem. 2005 May 6;280(18):18001-7. Epub 2005 Feb 28. PMID:15741158[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Avril LE, Di Martino-Ferrer M, Pignede G, Seman M, Gauthier F. Identification of the U-937 membrane-associated proteinase interacting with the V3 loop of HIV-1 gp120 as cathepsin G. FEBS Lett. 1994 May 23;345(1):81-6. PMID:8194606
- ↑ Maison CM, Villiers CL, Colomb MG. Proteolysis of C3 on U937 cell plasma membranes. Purification of cathepsin G. J Immunol. 1991 Aug 1;147(3):921-6. PMID:1861080
- ↑ Wasiluk KR, Skubitz KM, Gray BH. Comparison of granule proteins from human polymorphonuclear leukocytes which are bactericidal toward Pseudomonas aeruginosa. Infect Immun. 1991 Nov;59(11):4193-200. PMID:1937776
- ↑ de Garavilla L, Greco MN, Sukumar N, Chen ZW, Pineda AO, Mathews FS, Di Cera E, Giardino EC, Wells GI, Haertlein BJ, Kauffman JA, Corcoran TW, Derian CK, Eckardt AJ, Damiano BP, Andrade-Gordon P, Maryanoff BE. A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo. J Biol Chem. 2005 May 6;280(18):18001-7. Epub 2005 Feb 28. PMID:15741158 doi:10.1074/jbc.M501302200
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