title: The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor.
abstract: The crystal structure of human alpha-thrombin in complex with LY178550, a nonpeptidyl, active site-directed inhibitor, has been solved to 2.07 A resolution by the method of X-ray crystallography. The final model of the complex has a crystallographic R-value of 21.5% (Rfree = 23.1%) with 0.014 A and 2.4 degrees standard deviation from ideal bond lengths and angles, respectively. Well-defined electron density was observed for the inhibitor in the active site. The inhibitor binds to the active site in an L-shaped manner, mimicking the bound conformation of the tripeptide arginal series of thrombin inhibitors (Chirgadze NY et al., 1992, American Crystallographic Association Meeting 20: 116 [Abstr. PB311]). The basic amidine of LY178550 forms a salt bridge with Asp 189 within the specificity pocket, while the 4-benzylpiperidine side chain engages in a number of hydrophobic interactions at the S2 and S3 binding sites. The inhibitor does not interact in any fashion with the active site sequence Ser 214-Gly 216, as occurs with many of the inhibitors studied previously. The indole N-H of the inhibitor forms a hydrogen bond to the gamma-oxygen of the catalytic serine (Ser 195).
authors.affiliation: Lilly Research Laboratories, Indianapolis, Indiana 46285, USA. nyc@lilly.com
authors.forename: N Y
authors.initials: NY
authors.lastname: Chirgadze
authors.forename: D J
authors.initials: DJ
authors.lastname: Sall
authors.forename: V J
authors.initials: VJ
authors.lastname: Klimkowski
authors.forename: D K
authors.initials: DK
authors.lastname: Clawson
authors.forename: S L
authors.initials: SL
authors.lastname: Briggs
authors.forename: R
authors.initials: R
authors.lastname: Hermann
authors.forename: G F
authors.initials: GF
authors.lastname: Smith
authors.forename: D S
authors.initials: DS
authors.lastname: Gifford-Moore
authors.forename: J P
authors.initials: JP
authors.lastname: Wery
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006629:Hirudins / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry*; D011487:Protein Conformation; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D006629:Hirudins; D007211:Indoles; C107737:LY 178550; D010446:Peptide Fragments; D010880:Piperidines; C062510:hirugen; D013917:Thrombin