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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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* Residue conservation analysis
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Enzyme class:
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Chains L, H:
E.C.3.4.21.5
- thrombin.
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Reaction:
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Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.
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DOI no:
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Protein Sci
5:221-228
(1996)
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PubMed id:
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Crystallographic determination of the structures of human alpha-thrombin complexed with BMS-186282 and BMS-189090.
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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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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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Selected figure(s)
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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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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G.De Simone,
A.Lombardi,
S.Galdiero,
F.Nastri,
R.Della Morte,
N.Staiano,
C.Pedone,
M.Bolognesi,
and
V.Pavone
(1998).
Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex.
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Protein Sci,
7,
243-253.
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PDB code:
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K.Kamata,
H.Kawamoto,
T.Honma,
T.Iwama,
and
S.H.Kim
(1998).
Structural basis for chemical inhibition of human blood coagulation factor Xa.
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Proc Natl Acad Sci U S A,
95,
6630-6635.
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PDB codes:
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N.Y.Chirgadze,
D.J.Sall,
V.J.Klimkowski,
D.K.Clawson,
S.L.Briggs,
R.Hermann,
G.F.Smith,
D.S.Gifford-Moore,
and
J.P.Wery
(1997).
The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor.
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Protein Sci,
6,
1412-1417.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
