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PDBsum entry 1xxd
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Blood clotting/hydrolase inhibitor
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PDB id
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1xxd
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References listed in PDB file
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Key reference
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Title
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Crystal structures of the fxia catalytic domain in complex with ecotin mutants reveal substrate-Like interactions.
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Authors
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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,
J.E.Strickler.
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Ref.
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J Biol Chem, 2005,
280,
4704-4712.
[DOI no: ]
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PubMed id
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Abstract
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Thrombosis can lead to life-threatening conditions such as acute myocardial
infarction, pulmonary embolism, and stroke. Although commonly used
anti-coagulant drugs, such as low molecular weight heparin and warfarin, are
effective, they carry a significant risk of inducing severe bleeding
complications, and there is a need for safer drugs. Activated Factor XI (FXIa)
is a key enzyme in the amplification phase of the coagulation cascade.
Anti-human FXI antibody significantly reduces thrombus growth in a baboon
thrombosis model without bleeding problems (Gruber, A., and Hanson, S. R. (2003)
Blood 102, 953-955). Therefore, FXIa is a potential target for anti-thrombosis
therapy. To determine the structure of FXIa, we derived a recombinant catalytic
domain of FXI, consisting of residues 370-607 (rhFXI370-607). Here we report the
first crystal structure of rhFXI370-607 in complex with a substitution mutant of
ecotin, a panserine protease protein inhibitor secreted by Escherichia coli, to
2.2 A resolution. The presence of ecotin not only assisted in the
crystallization of the enzyme but also revealed unique structural features in
the active site of FXIa. Subsequently, the sequence from P5 to P2' in ecotin was
mutated to the FXIa substrate sequence, and the structures of the
rhFXI370-607-ecotin mutant complexes were determined. These structures provide
us with an understanding of substrate binding interactions of FXIa, the
structural information essential for the structure-based design of
FXIa-selective inhibitors.
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Figure 1.
FIG. 1. Stereoview of the crystal structure of
rhFXI[370-607]-ecotinM84R. A, a C  trace of
rhFXI[370-607]-ecotinM84R tetramer. The ecotinM84R molecules are
colored in blue and yellow, and the rhFXI[370-607] molecules are
colored in green and red. The N and C termini of each molecule
are labeled in the same color as the molecule. The primary and
secondary binding sites between rhFXI[370-607] and ecotinM84R
are indicated by arrows. B, a ribbon diagram of the catalytic
domain of FXIa in the rhFXI[370-607]-ecotinM84R crystal
structure. The helices are colored in
purple and  sheets are in green. A
few key residues, discussed in the text, are presented in a
ball-and-stick representation with CPK coloring. The N and C
termini are indicated. All figures were prepared with DINO
(www.dino3.org) and Povray (www.povray.org).
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Figure 3.
FIG. 3. Stereoview of the active site in the
rhFXI[370-607]-ecotinM84R structure. rhFXI[370-607] is in a
surface representation with the following color scheme: basic
residues in blue, acidic residues in red; polar residues in
yellow, and all others in white. Residues 78-88 of ecotinM84R,
labeled as P[7] to P[4'] are shown as a stick figure with CPK
coloring.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
4704-4712)
copyright 2005.
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