1BHX: X-RAY STRUCTURE OF THE COMPLEX OF HUMAN ALPHA THROMBIN WITH THE INHIBITOR SDZ 229-357

Citation:
Abstract
We have designed, synthesized, and tested in vitro a novel class of noncovalent thrombin inhibitors. The main feature of these inhibitors is a 6,5-fused bicyclic core structure that fills the S2 pocket of the active site of thrombin. The bicycle introduces conformational constraint into the ligand and locks the Xaa-Pro amide bond into the desired trans configuration. Among the known ring systems, we selected by molecular modeling the 7-thiaindolizidinones (BTD) as our basic template. The influence of several structural features was analyzed: the length of the argininal side chain, the stereochemistry at C6, and the importance of making optimal use of the S3 pocket. Finally, an X-ray crystal structure of inhibitor 15 bound to thrombin was obtained at a resolution of 2.3 A. These designed thrombin inhibitors, which were prepared by an efficient synthesis, showed high selectivity over trypsin and other serine proteases. Further derivation based on the information obtained by X-ray crystallography should certainly allow to improve the potency.
PDB ID: 1BHXDownload
MMDB ID: 8649
PDB Deposition Date: 1998/6/10
Updated in MMDB: 2011/11
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 1BHX: tetrameric; determined by author
Molecular Components in 1BHX
Label Count Molecule
Proteins (4 molecules)
1
Alpha Thrombin(Gene symbol: F2)
Molecule annotation
1
Alpha Thrombin(Gene symbol: F2)
Molecule annotation
1
Alpha Thrombin(Gene symbol: F2)
Molecule annotation
1
Alpha Thrombin
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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