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* Residue conservation analysis
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Enzyme class:
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Chains A, L:
E.C.3.4.21.6
- coagulation factor Xa.
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Reaction:
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Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.
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DOI no:
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Biochemistry
39:12534-12542
(2000)
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PubMed id:
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Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa.
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M.Adler,
D.D.Davey,
G.B.Phillips,
S.H.Kim,
J.Jancarik,
G.Rumennik,
D.R.Light,
M.Whitlow.
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ABSTRACT
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Factor Xa plays a critical role in the formation of blood clots. This serine
protease catalyzes the conversion of prothrombin to thrombin, the first joint
step that links the intrinsic and extrinsic coagulation pathways. There is
considerable interest in the development of factor Xa inhibitors for the
intervention in thrombic diseases. This paper presents the structure of the
inhibitor ZK-807834, also known as CI-1031, bound to factor Xa and provides the
details of the protein purification and crystallization. Results from mass
spectrometry indicate that the factor Xa underwent autolysis during
crystallization and the first EGF-like domain was cleaved from the protein. The
crystal structure of the complex shows that the amidine of ZK-807834 forms a
salt bridge with Asp189 in the S1 pocket and the basic imidazoline fits snugly
into the S4 site. The central pyridine ring provides a fairly rigid linker
between these groups. This rigidity helps minimize entropic losses during
binding. In addition, the structure reveals new interactions that were not found
in the previous factor Xa/inhibitor complexes. ZK-807834 forms a strong hydrogen
bond between an ionized 2-hydroxy group and Ser195 of factor Xa. There is also
an aromatic ring-stacking interaction between the inhibitor and Trp215 in the S4
pocket. These interactions contribute to both the potency of this compound (K(I)
= 0.11 nM) and the >2500-fold selectivity against homologous serine proteases
such as trypsin.
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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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V.Hähnke,
A.Klenner,
F.Rippmann,
and
G.Schneider
(2011).
Pharmacophore alignment search tool: Influence of the third dimension on text-based similarity searching.
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J Comput Chem,
32,
1618-1634.
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Y.K.Lee,
and
M.R.Player
(2011).
Developments in factor Xa inhibitors for the treatment of thromboembolic disorders.
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Med Res Rev,
31,
202-283.
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K.Fujimura,
and
Y.Sasabuchi
(2010).
The role of fluorine atoms in a fluorinated prostaglandin agonist.
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ChemMedChem,
5,
1254-1257.
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S.K.Buddai,
J.M.Layzer,
G.Lu,
C.P.Rusconi,
B.A.Sullenger,
D.M.Monroe,
and
S.Krishnaswamy
(2010).
An anticoagulant RNA aptamer that inhibits proteinase-cofactor interactions within prothrombinase.
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J Biol Chem,
285,
5212-5223.
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T.Zögg,
and
H.Brandstetter
(2009).
Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa.
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Structure,
17,
1669-1678.
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PDB codes:
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X.Li,
X.He,
B.Wang,
and
K.Merz
(2009).
Conformational variability of benzamidinium-based inhibitors.
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J Am Chem Soc,
131,
7742-7754.
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Y.Tanrikulu,
E.Proschak,
T.Werner,
T.Geppert,
N.Todoroff,
A.Klenner,
T.Kottke,
K.Sander,
E.Schneider,
R.Seifert,
H.Stark,
T.Clark,
and
G.Schneider
(2009).
Homology model adjustment and ligand screening with a pseudoreceptor of the human histamine H4 receptor.
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ChemMedChem,
4,
820-827.
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E.Proschak,
M.Rupp,
S.Derksen,
and
G.Schneider
(2008).
Shapelets: possibilities and limitations of shape-based virtual screening.
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J Comput Chem,
29,
108-114.
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N.Singh,
and
J.M.Briggs
(2008).
Molecular dynamics simulations of Factor Xa: insight into conformational transition of its binding subsites.
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Biopolymers,
89,
1104-1113.
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R.Abel,
T.Young,
R.Farid,
B.J.Berne,
and
R.A.Friesner
(2008).
Role of the active-site solvent in the thermodynamics of factor Xa ligand binding.
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J Am Chem Soc,
130,
2817-2831.
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S.Macedo-Ribeiro,
C.Almeida,
B.M.Calisto,
T.Friedrich,
R.Mentele,
J.Stürzebecher,
P.Fuentes-Prior,
and
P.J.Pereira
(2008).
Isolation, cloning and structural characterisation of boophilin, a multifunctional Kunitz-type proteinase inhibitor from the cattle tick.
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PLoS ONE,
3,
e1624.
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PDB code:
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T.Noguchi,
N.Tanaka,
T.Nishimata,
R.Goto,
M.Hayakawa,
A.Sugidachi,
T.Ogawa,
F.Asai,
and
K.Fujimoto
(2007).
Cinnamylindoline derivatives: synthesis and factor Xa (FXa) inhibitory activities.
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Chem Pharm Bull (Tokyo),
55,
1494-1504.
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K.M.Bromfield,
N.S.Quinsey,
P.J.Duggan,
and
R.N.Pike
(2006).
Approaches to selective peptidic inhibitors of factor Xa.
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Chem Biol Drug Des,
68,
11-19.
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T.Noguchi,
N.Tanaka,
T.Nishimata,
R.Goto,
M.Hayakawa,
A.Sugidachi,
T.Ogawa,
F.Asai,
Y.Matsui,
and
K.Fujimoto
(2006).
Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities.
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Chem Pharm Bull (Tokyo),
54,
163-174.
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H.Koshio,
F.Hirayama,
T.Ishihara,
R.Shiraki,
T.Shigenaga,
Y.Taniuchi,
K.Sato,
Y.Moritani,
Y.Iwatsuki,
S.Kaku,
N.Katayama,
T.Kawasaki,
Y.Matsumoto,
S.Sakamoto,
and
S.Tsukamoto
(2005).
Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors.
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Bioorg Med Chem,
13,
1305-1323.
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L.Jin,
P.Pandey,
R.E.Babine,
J.C.Gorga,
K.J.Seidl,
E.Gelfand,
D.T.Weaver,
S.S.Abdel-Meguid,
and
J.E.Strickler
(2005).
Crystal structures of the FXIa catalytic domain in complex with ecotin mutants reveal substrate-like interactions.
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J Biol Chem,
280,
4704-4712.
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PDB codes:
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J.A.Olsen,
D.W.Banner,
P.Seiler,
B.Wagner,
T.Tschopp,
U.Obst-Sander,
M.Kansy,
K.Müller,
and
F.Diederich
(2004).
Fluorine interactions at the thrombin active site: protein backbone fragments H-C(alpha)-C=O comprise a favorable C-F environment and interactions of C-F with electrophiles.
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Chembiochem,
5,
666-675.
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L.Chen,
C.Manithody,
L.Yang,
and
A.R.Rezaie
(2004).
Zymogenic and enzymatic properties of the 70-80 loop mutants of factor X/Xa.
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Protein Sci,
13,
431-442.
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A.Nayeem,
S.Krystek,
and
T.Stouch
(2003).
An assessment of protein-ligand binding site polarizability.
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Biopolymers,
70,
201-211.
|
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J.P.Ludeman,
R.N.Pike,
K.M.Bromfield,
P.J.Duggan,
J.Cianci,
B.Le Bonniec,
J.C.Whisstock,
and
S.P.Bottomley
(2003).
Determination of the P1', P2' and P3' subsite-specificity of factor Xa.
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Int J Biochem Cell Biol,
35,
221-225.
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C.Charron,
A.Kadri,
M.C.Robert,
R.Giegé,
and
B.Lorber
(2002).
Crystallization in the presence of glycerol displaces water molecules in the structure of thaumatin.
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Acta Crystallogr D Biol Crystallogr,
58,
2060-2065.
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PDB codes:
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N.S.Quinsey,
J.C.Whisstock,
B.Le Bonniec,
V.Louvain,
S.P.Bottomley,
and
R.N.Pike
(2002).
Molecular determinants of the mechanism underlying acceleration of the interaction between antithrombin and factor Xa by heparin pentasaccharide.
|
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J Biol Chem,
277,
15971-15978.
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T.R.Baird,
and
P.N.Walsh
(2002).
Activated platelets but not endothelial cells participate in the initiation of the consolidation phase of blood coagulation.
|
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J Biol Chem,
277,
28498-28503.
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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
codes are
shown on the right.
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Links
