1D4P

CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH 5-AMIDINOINDOLE-4-BENZYLPIPERIDINE INHIBITOR

Summary for 1D4P

• Entry DOI: 10.2210/pdb1d4p/pdb
• Related: 1D3D 1D3P 1D3Q 1D3T
• Descriptor: ALPHA-THROMBIN, HIRUGEN, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: thrombin; nonpeptidyl inhibitor; structure-based drug design, blood clotting, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 36052.97

Authors

Chirgadze, N.Y. (deposition date: 1999-10-04, release date: 1999-10-20, Last modification date: 2024-11-13)

Primary citation

Chirgadze, N.Y.,Sall, D.J.,Klimkowski, V.J.,Clawson, D.K.,Briggs, S.L.,Hermann, R.,Smith, G.F.,Gifford-Moore, D.S.,Wery, J.P.
The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor.
Protein Sci., 6:1412-1417, 1997

PubMed 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).

PubMed: 9232642

Experimental method

X-RAY DIFFRACTION (2.07 Å)