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PDBsum entry 1d3p
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Hydrolase/hydrolase inhibitor
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PDB id
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1d3p
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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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The crystal structures of human alpha-Thrombin complexed with active site-Directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors.
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Authors
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N.Y.Chirgadze,
D.J.Sall,
S.L.Briggs,
D.K.Clawson,
M.Zhang,
G.F.Smith,
R.W.Schevitz.
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Ref.
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Protein Sci, 2000,
9,
29-36.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structures of four active site-directed thrombin inhibitors, 1-4, in
a complex with human alpha-thrombin have been determined and refined at up to
2.0 A resolution using X-ray crystallography. These compounds belong to a
structurally novel family of inhibitors based on a 2,3-disubstituted
benzo[b]thiophene structure. Compared to traditional active-site directed
inhibitors, the X-ray crystal structures of these complexes reveal a novel
binding mode. Unexpectedly, the lipophilic benzo[b]thiophene nucleus of the
inhibitor appears to bind in the S1 specificity pocket. At the same time, the
basic amine of the C-3 side chain of the inhibitor interacts with the mostly
hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine
side chain at C-2 was found to point away from the active site, occupying a
location between the S1 and S1' sites. Together, the aromatic rings of the C-2
and C-3 side chains sandwich the indole ring of Trp60D contained in the thrombin
S2 insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin
residue numbering used in this study is equivalent to that reported for
chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New York:
Academic Press. pp 323-373).] In contrast to the binding mode of more classical
thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of
benzo[b]thiophene derivatives does not engage in hydrogen bond formation with
Gly216 of the thrombin active site. A detailed analysis of the three-dimensional
structures not only provides a clearer understanding of the interaction of these
agents with thrombin, but forms a foundation for rational structure-based drug
design. The use of the data from this study has led to the design of derivatives
that are up to 2,900-fold more potent than the screening hit 1.
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