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PDBsum entry 1wss
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Hydrolase/blood clotting
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PDB id
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1wss
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Contents |
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142 a.a.
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254 a.a.
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191 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure of human factor viia/tissue factor in complex with a peptide-Mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in p2 and p4.
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Authors
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S.Kadono,
A.Sakamoto,
Y.Kikuchi,
M.Oh-Eda,
N.Yabuta,
T.Koga,
K.Hattori,
T.Shiraishi,
M.Haramura,
H.Kodama,
Y.Ono,
T.Esaki,
H.Sato,
Y.Watanabe,
S.Itoh,
M.Ohta,
T.Kozono.
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Ref.
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Acta Crystallograph Sect F Struct Biol Cryst Commun, 2005,
61,
169-173.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of human factor VIIa/soluble tissue factor (FVIIa/sTF) in
complex with a highly selective peptide-mimetic FVIIa inhibitor which shows
1670-fold selectivity against thrombin inhibition has been solved at 2.6 A
resolution. The inhibitor is bound to FVIIa/sTF at the S1, S2 and S3 sites and
at the additional S1 subsite. Two charged groups, the amidino group in P2 and
the carboxylate group in P4, form ionic interactions with Asp60 and Lys192 of
FVIIa, respectively. Structural comparisons between factor VIIa and thrombin
show that thrombin has oppositely charged residues, Lys60F and Glu192, in the S2
site and the S1 subsites, respectively. These data suggest that the utilization
of the differences of charge distribution in the S2 site and the S1 subsites
between FVIIa and thrombin is critical for achieving high selectivity against
thrombin inhibition. These results will provide valuable information for the
structure-based drug design of specific inhibitors for FVIIa/TF.
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Figure 1.
Figure 1 Chemical structures of peptide-mimetic thrombin and
factor VIIa inhibitors. Values in parentheses refer to the ratio
against FVIIa/TF IC[50].
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Figure 4.
Figure 4 X-ray crystal structure of compound (2) bound to
factor VIIa/sTF. C atoms of compound (2) are shown in green.
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The above figures are
reprinted
from an Open Access publication published by the IUCr:
Acta Crystallograph Sect F Struct Biol Cryst Commun
(2005,
61,
169-173)
copyright 2005.
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