title: Unique binding of a novel synthetic inhibitor, N-[3-[4-[4-(amidinophenoxy)carbonyl]phenyl]-2-methyl-2-propenoyl]- N-allylglycine methanesulfonate, to bovine trypsin, revealed by the crystal structure of the complex.
abstract: Trypsin and N-[3-[4-[4-(amidinophenoxy)carbonyl]phenyl]-2-methyl-2-propenoyl]- N-allylglycine methanesulfonate (1), a newly designed and orally active synthetic trypsin inhibitor, were cocrystallized. The space group of the crystal is P2(1)2(1)2(1) with cell constants a = 63.74 A, b = 63.08 A, and c = 69.38 A, which is nearly identical to that of the orthorhombic crystal of guanidinobenzoyltrypsin. The structure was refined to a crystallographic residual R = 0.176. The refined model of the 1-trypsin complex provides the structural basis for the reaction mechanism of 1. On the basis of the present X-ray results, it is proposed that the potent inhibitory activity of 1 is mainly due to the formation of an acylated trypsin through an "inverse substrate mechanism" and its low rate of deacylation.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Odagaki
authors.forename: H
authors.initials: H
authors.lastname: Nakai
authors.forename: K
authors.initials: K
authors.lastname: Senokuchi
authors.forename: M
authors.initials: M
authors.lastname: Kawamura
authors.forename: N
authors.initials: N
authors.lastname: Hamanaka
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Tomoo
authors.forename: T
authors.initials: T
authors.lastname: Ishida
mesh_terms: D000501:Allylglycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001550:Benzamidines / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D002417:Cattle; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D015394:Molecular Structure; D013379:Substrate Specificity; D014357:Trypsin / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001550:Benzamidines; C095996:N-(3-(4-(4-(amidinophenoxy)carbonyl)phenyl)-2-methyl-2-propenoyl)-N-allylglycine; D014361:Trypsin Inhibitors; D000501:Allylglycine; D014357:Trypsin