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PDBsum entry 1h8i
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Hydrolase/hydrolase inhibitor
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PDB id
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1h8i
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Inhibition of human alpha-Thrombin by a phosphonate tripeptide proceeds via a metastable pentacoordinated phosphorus intermediate.
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Authors
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E.Skordalakes,
G.G.Dodson,
D.S.Green,
C.A.Goodwin,
M.F.Scully,
H.R.Hudson,
V.V.Kakkar,
J.J.Deadman.
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Ref.
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J Mol Biol, 2001,
311,
549-555.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 2.
Figure 2. Stereo view of the interactions of the
phosphonate moiety of the tripeptide inhibitor, compound 1, at
the active site of the enzyme human α-thrombin in complex I.
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Figure 7.
Figure 7. The overall α-thrombin reaction mechanism based
on the structures of complex I and complex II.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
311,
549-555)
copyright 2001.
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Secondary reference #1
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Title
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Inhibition of trypsin and thrombin by amino(4-Amidinophenyl)methanephosphonate diphenyl ester derivatives: X-Ray structures and molecular models.
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Authors
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J.A.Bertrand,
J.Oleksyszyn,
C.M.Kam,
B.Boduszek,
S.Presnell,
R.R.Plaskon,
F.L.Suddath,
J.C.Powers,
L.D.Williams.
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Ref.
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Biochemistry, 1996,
35,
3147-3155.
[DOI no: ]
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PubMed id
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