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* Residue conservation analysis
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PDB id:
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Hydrolase/inhibitor
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Title:
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Crystal structure of factor xa in complex with compound "1"
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Structure:
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Coagulation factor xa. Chain: a. Fragment: light chain, residues 126-234. Synonym: stuart factor, stuart-prower factor. Coagulation factor xa. Chain: b. Fragment: light chain, residues 235-488. Synonym: stuart factor, stuart-prower factor. Ec: 3.4.21.6
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Tissue: blood
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Biol. unit:
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Dimer (from PDB file)
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Resolution:
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2.20Å
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R-factor:
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0.207
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R-free:
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0.253
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Authors:
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M.Nazare,D.W.Will,H.Matter,H.Schreuder,K.Ritter,M.Urmann,M.Essrich, A.Bauer,M.Wagner,J.Czech,V.Laux,V.Wehner
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Key ref:
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M.Nazaré
et al.
(2005).
Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography.
J Med Chem,
48,
4511-4525.
PubMed id:
DOI:
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Date:
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11-Apr-05
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Release date:
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05-Apr-06
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PROCHECK
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Headers
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References
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Enzyme class:
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Chains A, B:
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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J Med Chem
48:4511-4525
(2005)
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PubMed id:
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Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography.
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M.Nazaré,
D.W.Will,
H.Matter,
H.Schreuder,
K.Ritter,
M.Urmann,
M.Essrich,
A.Bauer,
M.Wagner,
J.Czech,
M.Lorenz,
V.Laux,
V.Wehner.
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ABSTRACT
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Structure-activity relationships within a series of highly potent
2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are
described with particular emphasis on the structural requirements for addressing
subpockets of the factor Xa enzyme. Interactions with the subpockets were probed
by systematic substitution of the 2-carboxyindole scaffold, in combination with
privileged P1 and P4 substituents. Combining the most favorable substituents at
the indole nucleus led to the discovery of a remarkably potent factor Xa
inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of
inhibitors bound to factor Xa revealed substituent-dependent switching of the
inhibitor binding mode and provided a rationale for the SAR obtained. These
results underscore the key role played by the P1 ligand not only in determining
the binding affinity of the inhibitor by direct interaction but also in
modifying the binding mode of the whole scaffold, resulting in a nonlinear SAR.
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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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E.Perzborn,
S.Roehrig,
A.Straub,
D.Kubitza,
and
F.Misselwitz
(2011).
The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor.
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Nat Rev Drug Discov,
10,
61-75.
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H.G.Wallnoefer,
K.R.Liedl,
and
T.Fox
(2011).
A challenging system: Free energy prediction for factor Xa.
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J Comput Chem,
32,
1743-1752.
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A.Vulpetti,
N.Schiering,
and
C.Dalvit
(2010).
Combined use of computational chemistry, NMR screening, and X-ray crystallography for identification and characterization of fluorophilic protein environments.
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Proteins,
78,
3281-3291.
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PDB codes:
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H.G.Wallnoefer,
T.Fox,
K.R.Liedl,
and
C.S.Tautermann
(2010).
Dispersion dominated halogen-π interactions: energies and locations of minima.
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Phys Chem Chem Phys,
12,
14941-14949.
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Y.Kawasaki,
E.E.Chufan,
V.Lafont,
K.Hidaka,
Y.Kiso,
L.Mario Amzel,
and
E.Freire
(2010).
How much binding affinity can be gained by filling a cavity?
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Chem Biol Drug Des,
75,
143-151.
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PDB codes:
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Y.Lu,
Y.Wang,
and
W.Zhu
(2010).
Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design.
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Phys Chem Chem Phys,
12,
4543-4551.
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C.Krishnasamy,
A.Raghuraman,
L.B.Kier,
and
U.R.Desai
(2008).
Application of molecular connectivity and electro-topological indices in quantitative structure-activity analysis of pyrazole derivatives as inhibitors of factor xa and thrombin.
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Chem Biodivers,
5,
2609-2620.
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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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Y.Imaeda,
T.Miyawaki,
H.Sakamoto,
F.Itoh,
N.Konishi,
K.Hiroe,
M.Kawamura,
T.Tanaka,
and
K.Kubo
(2008).
Discovery of sulfonylalkylamides: A new class of orally active factor Xa inhibitors.
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Bioorg Med Chem,
16,
2243-2260.
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Y.N.Imai,
Y.Inoue,
I.Nakanishi,
and
K.Kitaura
(2008).
Cl-pi interactions in protein-ligand complexes.
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Protein Sci,
17,
1129-1137.
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G.Faure,
V.T.Gowda,
and
R.C.Maroun
(2007).
Characterization of human coagulation factor Xa-binding site on Viperidae snake venom phospholipases A2 by affinity binding studies and molecular bioinformatics.
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BMC Struct Biol,
7,
82.
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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
