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Protein Science, Vol 6, Issue 7 1412-1417, Copyright © 1997 by Cold Spring Harbor Laboratory Press

ARTICLE

The crystal structure of human {alpha}-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor

N. Y. CHIRGADZE, D. J. SALL, V. J. KLIMKOWSKI, D. K. CLAWSON, S. L. BRIGGS, R. HERMANN, G. F. SMITH, D. S. GIFFORD-MOORE and J. P. WERY
Lilly Research Laboratories, Indianapolis, Indiana 46285

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% (R(free) = 23.1%) with 0.014 A and 2.4{deg} 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 S(2) and S(3) 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).
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