title: Structure of human alpha-thrombin complexed with RWJ-51438 at 1.7 A: unusual perturbation of the 60A-60I insertion loop.
abstract: The three-dimensional structure of the ternary complex consisting of human alpha-thrombin, hirugen and the active-site inhibitor RWJ-51438 has been determined at 1.7 A resolution. The crystals of the complex belong to the orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 62.98, b = 117.52, c = 47.99 A. The refined R and R(free) values are 0.196 and 0.232, respectively. The ketone carbonyl group of the inhibitor is covalently linked to the hydroxyl O atom of Ser195, forming a tetrahedral intermediate hemiketal structure; the benzothiazole ring N atom of RWJ-51438 forms a hydrogen bond with His57. Surprisingly, the carboxylate substituent on the benzothiazole group forms salt bridges with Lys60F NZ and the NZ of the symmetry-related residues Lys236 and Lys240, which introduces steric effects that perturb the 60A-60I insertion loop, especially at residues Trp60D and Phe60H.
authors.affiliation: Center for Macromolecular Crystallography, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.
authors.forename: R
authors.initials: R
authors.lastname: Recacha
authors.forename: M J
authors.initials: MJ
authors.lastname: Costanzo
authors.forename: B E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: M
authors.initials: M
authors.lastname: Carson
authors.forename: L
authors.initials: L
authors.lastname: DeLucas
authors.forename: D
authors.initials: D
authors.lastname: Chattopadhyay
mesh_terms: D000991:Antithrombins / Q000737:chemistry*; D052160:Benzothiazoles; D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D011487:Protein Conformation; D013844:Thiazoles / Q000737:chemistry*; D013917:Thrombin / Q000737:chemistry*
chemical_list: D000991:Antithrombins; D052160:Benzothiazoles; D009842:Oligopeptides; C419862:RWJ 51438; D013844:Thiazoles; D013917:Thrombin