THE CRYSTAL-STRUCTURE OF HUMAN ALPHA-THROMBIN COMPLEXED WITH LY178550, A NONPEPTIDYL, ACTIVE-SITE-DIRECTED INHIBITOR

The crystal structure of human a-thrombin in complex with LY178550, a nonpeptidyl, active site-directed inhibitor, has been solved to 2.07 A ngstrom resolution by the method of X-ray crystallography. The final m odel of the complex has a crystallographic R-value of 21.5% (R-free = 23.1%) with 0.014 Angstrom and 2.4 degrees standard deviation from ide al bond lengths and angles, respectively. Well-defined electron densit y was observed for the inhibitor in the active site. The inhibitor bin ds to the active site in an L-shaped manner, mimicking the bound confo rmation of the tripeptide arginal series of thrombin inhibitors (Chirg adze NY et al., 1992, American Crystallographic Association Meeting 20 :116 [Abstr. PB311]). The basic amidine of LY178550 forms a salt bridg e with Asp 189 within the specificity pocket, while the 4-benzylpiperi dine side chain engages in a number of hydrophobic interactions at the S-2 and S-3 binding sites. The inhibitor does not interact in any fas hion with the active site sequence Ser 214-Gly 216, as occurs with man y of the inhibitors studied previously. The indole N-H of the inhibito r forms a hydrogen bond to the gamma-oxygen of the catalytic serine (S er 195).