title: Crystal structure of cathepsin B inhibited with CA030 at 2.0-A resolution: A basis for the design of specific epoxysuccinyl inhibitors.
abstract: Crystals of cysteine protease human cathepsin B inhibited with CA030 (ethyl ester of epoxysuccinyl-Ile-Pro-OH) [Murata, M., et al. (1991) FEBS Lett. 280, 307-310; Towatari, T., et al. (1991) FEBS Lett. 280, 311-315] were isomorphous to a previous published structure of cathepsin B [Musil, D., et al. (1991) EMBO J. 10, 2321-2330]. The crystal structure of the complex was refined at 2.0-A resolution to an R-value of 0.194. CA030 is well-defined in the electron density. The Ile-Pro-OH part of CA030 mimics a substrate P1' and P2' residues. The structure thus reveals for the first time a substratelike interaction in the S1' and S2' sites of a papain-like cysteine protease. The CA030 ethyl ester group occupies the S2 site. The structure confirms the role of residues His 110 and His 111 as the receptors of a peptidic substrate C-terminal carboxylic group. The structure suggests that an epoxysuccinyl fragment can be used to extend binding into primed and nonprimed substrate binding sites of a papain-like cysteine protease.
authors.affiliation: Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, Ljubljana, Slovenia.
authors.forename: D
authors.initials: D
authors.lastname: Turk
authors.forename: M
authors.initials: M
authors.lastname: Podobnik
authors.forename: T
authors.initials: T
authors.lastname: Popovic
authors.forename: N
authors.initials: N
authors.lastname: Katunuma
authors.forename: W
authors.initials: W
authors.lastname: Bode
authors.forename: R
authors.initials: R
authors.lastname: Huber
authors.forename: V
authors.initials: V
authors.lastname: Turk
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry; D008969:Molecular Sequence Data; D011487:Protein Conformation
chemical_list: D004151:Dipeptides; C068249:N-(3-ethoxycarbonyloxirane-2-carbonyl)-isoleucyl-proline; D002401:Cathepsin B; D007930:Leucine; C024974:E 64