The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor.
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).
Chirgadze
N Y
NY
Lilly Research Laboratories, Indianapolis, Indiana 46285, USA. nyc@lilly.com
Sall
D J
DJ
Klimkowski
V J
VJ
Clawson
D K
DK
Briggs
S L
SL
Hermann
R
R
Smith
G F
GF
Gifford-Moore
D S
DS
Wery
J P
JP
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*
D006629:Hirudins; D007211:Indoles; C107737:LY 178550; D010446:Peptide Fragments; D010880:Piperidines; C062510:hirugen; D013917:Thrombin