1GFW

THE 2.8 ANGSTROM CRYSTAL STRUCTURE OF CASPASE-3 (APOPAIN OR CPP32)IN COMPLEX WITH AN ISATIN SULFONAMIDE INHIBITOR.

Replaces:  1QA8

Summary for 1GFW

• Entry DOI: 10.2210/pdb1gfw/pdb
• Related: 1cp3 1pau
• Descriptor: CASPASE-3 (APOPAIN, P20), CASPASE-3 (APOPAIN, P10), 1-METHYL-5-(2-PHENOXYMETHYL-PYRROLIDINE-1-SULFONYL)-1H-INDOLE-2,3-DIONE, ... (4 entities in total)
• Functional Keywords: caspase inhibitor, caspase-3, apopain, istin sulfonamide, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 28463.49

Authors

Concha, N.O.,Janson, C.A. (deposition date: 2000-06-16, release date: 2000-06-23, Last modification date: 2023-12-27)

Primary citation

Lee, D.,Long, S.A.,Adams, J.L.,Chan, G.,Vaidya, K.S.,Francis, T.A.,Kikly, K.,Winkler, J.D.,Sung, C.M.,Debouck, C.,Richardson, S.,Levy, M.A.,DeWolf Jr., W.E.,Keller, P.M.,Tomaszek, T.,Head, M.S.,Ryan, M.D.,Haltiwanger, R.C.,Liang, P.H.,Janson, C.A.,McDevitt, P.J.,Johanson, K.,Concha, N.O.,Chan, W.,Abdel-Meguid, S.S.,Badger, A.M.,Lark, M.W.,Nadeau, D.P.,Suva, L.J.,Gowen, M.,Nuttall, M.E.
Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality.
J.Biol.Chem., 275:16007-16014, 2000

PubMed Abstract: Caspases have been strongly implicated to play an essential role in apoptosis. A critical question regarding the role(s) of these proteases is whether selective inhibition of an effector caspase(s) will prevent cell death. We have identified potent and selective non-peptide inhibitors of the effector caspases 3 and 7. The inhibition of apoptosis and maintenance of cell functionality with a caspase 3/7-selective inhibitor is demonstrated for the first time, and suggests that targeting these two caspases alone is sufficient for blocking apoptosis. Furthermore, an x-ray co-crystal structure of the complex between recombinant human caspase 3 and an isatin sulfonamide inhibitor has been solved to 2.8-A resolution. In contrast to previously reported peptide-based caspase inhibitors, the isatin sulfonamides derive their selectivity for caspases 3 and 7 by interacting primarily with the S(2) subsite, and do not bind in the caspase primary aspartic acid binding pocket (S(1)). These inhibitors blocked apoptosis in murine bone marrow neutrophils and human chondrocytes. Furthermore, in camptothecin-induced chondrocyte apoptosis, cell functionality as measured by type II collagen promoter activity is maintained, an activity considered essential for cartilage homeostasis. These data suggest that inhibiting chondrocyte cell death with a caspase 3/7-selective inhibitor may provide a novel therapeutic approach for the prevention and treatment of osteoarthritis, or other disease states characterized by excessive apoptosis.

PubMed: 10821855
DOI: 10.1074/jbc.275.21.16007

Experimental method

X-RAY DIFFRACTION (2.8 Å)