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The crystal structure of human α‐thrombin complexed with LY178550, a nonpeptidyl, active site‐directed inhibitor
Author(s) -
Chirgadze Nickolay Y.,
Sall Daniel J.,
Klimkowski Valentine J.,
Clawson David K.,
Briggs Steve L.,
Hermann Robert,
Smith Gerald F.,
GiffordMoore Donetta S.,
Wery JeanPierre
Publication year - 1997
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.5560060705
Subject(s) - active site , chemistry , stereochemistry , serine protease , binding site , hydrogen bond , tripeptide , salt bridge , crystallography , crystal structure , thrombin , amidine , protein structure , molecule , enzyme , peptide , biochemistry , biology , protease , platelet , organic chemistry , gene , mutant , immunology
The crystal structure of human α‐thrombin in complex with LY178550, a nonpeptidyl, active site‐directed inhibitor, has been solved to 2.07 α 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 Å and 2.4° 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 γ‐oxygen of the catalytic serine (Ser 195).