 |
PDBsum entry 1xka
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Blood coagulation factor
|
PDB id
|
|
|
|
1xka
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for chemical inhibition of human blood coagulation factor xa.
|
|
|
Authors
|
|
K.Kamata,
H.Kawamoto,
T.Honma,
T.Iwama,
S.H.Kim.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 1998,
95,
6630-6635.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged as an
alternative (to thrombin) target for drug discovery for thromboembolic diseases.
An inhibitor has been synthesized and the crystal structure of the complex
factor Xa and the inhibitor has been determined by
crystallographic methods in two different crystal forms to 2.3- and 2.4-A
resolution. The racemic mixture of inhibitor FX-2212,
(2RS)-(3'-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid, inhibits
factor Xa activity by 50% at 272 nM in vitro. The S-isomer of FX-2212 (FX-2212a)
was found to bind to the active site of factor Xa in both crystal forms. The
biphenylamidine of FX-2212a occupies the S1-pocket, and the pyridine ring makes
hydrophobic interactions with the factor Xa aryl-binding site. Several water
molecules meditate inhibitor binding to residues in the active site. In contrast
factor Xa in complex with a naphthyl inhibitor DX-9065a,
two epidermal growth factor-like domains of factor Xa are well ordered in both
our crystal forms as well as the region between the two domains, which recently
was found to be the binding site of the effector cell protease receptor-1. This
structure provides a basis for designing next generation inhibitors of factor Xa.
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Chemical formulae of the FX-2212a inhibitor
(2S)-(3'-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid
and the DX9065a
(2S)-{4-[1-acetimidoyl-(3S)-pyrrolidinyl]oxyphenyl}-3-(7-amidino-2-naphthyl)propionic
acid. Schematic drawing of the interactions between two
inhibitors, DX9065a and FX-2212a, and factor Xa. Hydrogen bonds
are shown as thin dashed lines, and hydrophobic interactions are
shown as thick dashed lines. In the case of Q192, the aliphatic
chain portion of Q192 makes the hydrophobic interaction. The
symbol "  " indicates
that the two interacting aromatic groups are not stacked but are
perpendicular to each other.
|
|
Figure 5.
Fig. 5. (a) Stereo view of the electron density for
FX-2212a in difference electron density maps (contoured at 1.6
 )
calculated after modeling the first EGF domain and the simulated
annealing refinement. The final structure is superimposed. (b)
Binding interactions of FX-2212a (magenta ball and stick) with
Des[1-44] factor Xa in the form 1 crystal. The C  backbone is
shown in blue, and residues involved in interaction are shown as
a yellow ball-and-stick model. Conserved hydrogen bonds in the
three crystallographically independent molecules are shown in
green and a unique hydrogen bond in this interaction is shown in
orange.
|
|
|
|
|
|
Secondary reference #1
|
|
|
Title
|
|
X-Ray structure of active site-Inhibited clotting factor xa. Implications for drug design and substrate recognition.
|
|
|
Authors
|
|
H.Brandstetter,
A.Kühne,
W.Bode,
R.Huber,
W.Von der saal,
K.Wirthensohn,
R.A.Engh.
|
|
|
Ref.
|
|
J Biol Chem, 1996,
271,
29988-29992.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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.
|
|
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.
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from the ASBMB
|
|
|
Secondary reference #2
|
|
|
Title
|
|
Structure of human des(1-45) factor xa at 2.2 a resolution.
|
|
|
Authors
|
|
K.Padmanabhan,
K.P.Padmanabhan,
A.Tulinsky,
C.H.Park,
W.Bode,
R.Huber,
D.T.Blankenship,
A.D.Cardin,
W.Kisiel.
|
|
|
Ref.
|
|
J Mol Biol, 1993,
232,
947-966.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
