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PDBsum entry 1ca8
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Hydrolase/hydrolase inhibitor
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PDB id
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1ca8
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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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Highly selective mechanism-Based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes.
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Authors
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R.Krishnan,
E.Zhang,
K.Hakansson,
R.K.Arni,
A.Tulinsky,
M.S.Lim-Wilby,
O.E.Levy,
J.E.Semple,
T.K.Brunck.
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Ref.
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Biochemistry, 1998,
37,
12094-12103.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structures of three highly potent and selective low-molecular weight
rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined
and refined to R values 0.152-0. 170 at 1.8-2.1 A resolution. Since the
selectivity of two of the inhibitors was >1600 with respect to trypsin, the
structures of trypsin-inhibited complexes of these inhibitors were also
determined (R = 0.142-0.157 at 1.9-2.1 A resolution). The selectivity appears to
reside in the inability of a benzenesulfonamide group to bind at the equivalent
of the D-enantiomorphic S3 site of thrombin, which may be related to the lack of
a 60-insertion loop in trypsin. All the inhibitors have a novel lactam moiety at
the P3 position, while the two with greatest trypsin selectivity have a
guanidinopiperidyl group at the P1 position that binds in the S1 specificity
site. Differences in the binding constants of these inhibitors are correlated
with their interactions with thrombin and trypsin. The kinetics of inhibition
vary from slow to fast with thrombin and are fast in all cases with trypsin. The
kinetics are examined in terms of the slow formation of a stable
transition-state complex in a two-step mechanism. The structures of both
thrombin and trypsin complexes show similar well-defined transition states in
the S1 site and at the electrophilic carbon atom and Ser195OG. The trypsin
structures, however, suggest that the first step in a two-step kinetic mechanism
may involve formation of a weak transition-state complex, rather than binding
dominated by the P2-P4 positions.
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