1H8D: X-ray Structure Of The Human Alpha-thrombin Complex With A Tripeptide Phosphonate Inhibitor

Citation:
Abstract
X-ray crystallographic studies of human alpha-thrombin with a novel synthetic inhibitor, an acyl (alpha-aminoalkyl)phosphonate, reveal the existence of a pentacovalent phosphorus intermediate state. Crystal structures of the complex of alpha-thrombin with the phosphonate compound were determined independently using crystals of different ages. The first structure, solved from a crystal less than seven days old, showed a pentacoordinated phosphorus moiety. The second structure, determined from a crystal that was 12 weeks old, showed a tetracoordinated phosphorus moiety. In the first structure, a water molecule, made nucleophilic by coordination to His57 of alpha-thrombin, is bonded to the pentacoordinated phosphorus atom. Its position is approximately equivalent to that occupied by the water molecule responsible for hydrolytic deacylation during normal hydrolysis. The pentacoordinated phosphorus adduct collapses to give the expected pseudo tetrahedral complex, where the phosphorus atom is covalently bonded to Ser195 O(gamma). The crystallographic data presented here therefore suggest that the covalent bond formed between the inhibitor's phosphorus atom and O(gamma) of Ser195 proceeds via an addition-elimination mechanism, which involves the formation of a pentacoordinate intermediate.
PDB ID: 1H8DDownload
MMDB ID: 105302
PDB Deposition Date: 2001/2/1
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.4  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 1H8D: trimeric; determined by software (PISA)
Molecular Components in 1H8D
Label Count Molecule
Proteins (3 molecules)
1
Thrombin(Gene symbol: F2)
Molecule annotation
1
Hirudin I
Molecule annotation
1
Thrombin(Gene symbol: F2)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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