1t32: Difference between revisions

[[Image:1t32.gif|left|200px]]<br /><applet load="1t32" size="350" color="white" frame="true" align="right" spinBox="true"  

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.

1T32 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=OHH:'>OHH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Cathepsin_G Cathepsin G], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.20 3.4.21.20] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T32 OCA].  

[[Category: Abraham, W M.]]

[[Category: Cera, E Di.]]

[[Category: Corcoran, T W.]]

[[Category: Damiano, B P.]]

[[Category: Derian, C K.]]

[[Category: Eckardt, A J.]]

[[Category: Garavilla, L de.]]

[[Category: Giardino, E C.]]

[[Category: Greco, M N.]]

[[Category: Haertlein, B J.]]

[[Category: Kauffman, J A.]]

[[Category: Maryanoff, B E.]]

[[Category: Mathews, F S.]]

[[Category: Pineda, A O.]]

[[Category: Wells, G I.]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:09:18 2008''