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PDBsum entry 1fax
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Coagulation factor
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PDB id
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1fax
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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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X-Ray structure of active site-Inhibited clotting factor xa. Implications for drug design and substrate recognition.
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Authors
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H.Brandstetter,
A.Kühne,
W.Bode,
R.Huber,
W.Von der saal,
K.Wirthensohn,
R.A.Engh.
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Ref.
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J Biol Chem, 1996,
271,
29988-29992.
[DOI no: ]
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PubMed id
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Abstract
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The 3.0-A resolution x-ray structure of human des-Gla-coagulation factor Xa
(fXa) has been determined in complex with the synthetic inhibitor DX-9065a. The
binding geometry is characterized primarily by two interaction sites: the
naphthamidine group is fixed in the S1 pocket by a typical salt bridge to
Asp-189, while the pyrrolidine ring binds in the unique aryl-binding site (S4)
of fXa. Unlike the large majority of inhibitor complexes with serine
proteinases, Gly-216 (S3) does not contribute to hydrogen bond formation. In
contrast to typical thrombin binding modes, the S2 site of fXa cannot be used by
DX-9065a since it is blocked by Tyr-99, and the aryl-binding site (S4) of fXa is
lined by carbonyl oxygen atoms that can accommodate positive charges. This has
implications for natural substrate recognition as well as for drug design.
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Figure 1.
Fig. 1. Chemical formula of the DX-9065a inhibitor:
(2S)-{4-[1-acetimidoyl-(3S)-pyrrolidinyl]-oxyphenyl}-3-(7-amidino-2-naphthyl)propionic^
acid hydrochloride pentahydrate.
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Figure 3.
Fig. 3. Binding interactions of DX-9065a with fXa. The C^
 plot
and side chains involved in inhibitor binding of DX-9065a-bound^
fXa (yellow) are superimposed with the corresponding atoms of^
arginine-bound fXa (turquoise). The ligand-induced structural
changes at the S1-binding site may be seen at the side chain of^
Asp-189 and along the main chain at Gln-192. The hydrophobic
sleeve^ at the aryl-binding site (S4) is also apparent, with the
cation hole formed by Glu-97 and the carbonyl oxygens of Glu-97
and Lys-96^ at the back.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(1996,
271,
29988-29992)
copyright 1996.
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Secondary reference #1
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Title
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X-Ray structure of clotting factor ixa: active site and module structure related to xase activity and hemophilia b.
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Authors
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H.Brandstetter,
M.Bauer,
R.Huber,
P.Lollar,
W.Bode.
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Ref.
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Proc Natl Acad Sci U S A, 1995,
92,
9796-9800.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Structure of human des(1-45) factor xa at 2.2 a resolution.
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Authors
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K.Padmanabhan,
K.P.Padmanabhan,
A.Tulinsky,
C.H.Park,
W.Bode,
R.Huber,
D.T.Blankenship,
A.D.Cardin,
W.Kisiel.
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Ref.
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J Mol Biol, 1993,
232,
947-966.
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PubMed id
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Secondary reference #3
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Title
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A novel factor xa inhibitor: structure-Activity relationships and selectivity between factor xa and thrombin.
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Authors
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S.Katakura,
T.Nagahara,
T.Hara,
M.Iwamoto.
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Ref.
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Biochem Biophys Res Commun, 1993,
197,
965-972.
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PubMed id
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