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PDBsum entry 1bmm
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Hydrolase/hydrolase inhibitor
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PDB id
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1bmm
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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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Crystallographic determination of the structures of human alpha-Thrombin complexed with bms-186282 and bms-189090.
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Authors
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M.F.Malley,
L.Tabernero,
C.Y.Chang,
S.L.Ohringer,
D.G.Roberts,
J.Das,
J.S.Sack.
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Ref.
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Protein Sci, 1996,
5,
221-228.
[DOI no: ]
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PubMed id
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Abstract
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The crystallographic structures of the ternary complexes of human alpha-thrombin
with hirugen (a sulfated hirudin fragment) and the small-molecule active site
thrombin inhibitors BMS-186282 and BMS-189090 have been determined at 2.6 and
2.8 A. In both cases, the inhibitors, which adopt very similar bound
conformations, bind in an antiparallel beta-strand arrangement relative to the
thrombin main chain in a manner like that reported for PPACK,
D-Phe-Pro-Arg-CH2Cl. They do, however, exhibit differences in the binding of the
alkyl guanidine moiety in the specificity pocket. Numerous hydrophilic and
hydrophobic interactions serve to stabilize the inhibitors in the binding
pocket. Although PPACK forms covalent bonds to both serine and the histidine of
the catalytic triad of thrombin, neither BMS-186282 nor BMS-189090 bind
covalently and only BMS-186282 forms a hydrogen bond to the serine of the
catalytic triad. Both inhibitors bind with high affinity (Ki = 79 nM and 3.6 nM,
respectively) and are highly selective for thrombin over trypsin and other
serine proteases.
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Figure 1.
Fig. 1. Structures of PPACK andNAPAPand the development of
BMS-186282 and BMS-189090 from MD-805 and BMS-183507.
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Figure 4.
Fig. 4. Final (2F, - F, I omitelectrondensitymaps at the active of
cy-thrombincomplexedwith (A) BMS-186282 and (B) BMS-189D90 su-
perimposewiththefinalthree-dimensionalstructures of the inhibitors.
Electron densitymapswerecalculatedusingX-PLOR(Briinger,1989).
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(1996,
5,
221-228)
copyright 1996.
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