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Contents |
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43 a.a.
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259 a.a.
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412 a.a.
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* Residue conservation analysis
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PDB id:
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Hydrolase/blood clotting
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Title:
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2.5a crystal structure of the antithrombin-thrombin-heparin ternary complex
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Structure:
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Thrombin. Chain: l. Fragment: thrombin light chain. Synonym: coagulation factor ii. Engineered: yes. Mutation: yes. Thrombin. Chain: h. Fragment: thrombin heavy chain, serine protease.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: f2. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Gene: serpinc1, at3. Expression_system_taxid: 10029
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Biol. unit:
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Trimer (from
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Resolution:
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2.50Å
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R-factor:
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0.208
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R-free:
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0.245
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Authors:
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W.Li,D.J.Johnson,C.T.Esmon,J.A.Huntington
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Key ref:
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W.Li
et al.
(2004).
Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin.
Nat Struct Mol Biol,
11,
857-862.
PubMed id:
DOI:
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Date:
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19-May-04
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Release date:
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17-Aug-04
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PROCHECK
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Headers
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References
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P00734
(THRB_HUMAN) -
Prothrombin from Homo sapiens
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Seq:
Struc:
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622 a.a.
43 a.a.
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Enzyme class:
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Chains L, H:
E.C.3.4.21.5
- thrombin.
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Reaction:
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Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.
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DOI no:
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Nat Struct Mol Biol
11:857-862
(2004)
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PubMed id:
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Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin.
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W.Li,
D.J.Johnson,
C.T.Esmon,
J.A.Huntington.
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ABSTRACT
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The maintenance of normal blood flow depends completely on the inhibition of
thrombin by antithrombin, a member of the serpin family. Antithrombin circulates
at a high concentration, but only becomes capable of efficient thrombin
inhibition on interaction with heparin or related glycosaminoglycans. The
anticoagulant properties of therapeutic heparin are mediated by its interaction
with antithrombin, although the structural basis for this interaction is
unclear. Here we present the crystal structure at a resolution of 2.5 A of the
ternary complex between antithrombin, thrombin and a heparin mimetic (SR123781).
The structure reveals a template mechanism with antithrombin and thrombin bound
to the same heparin chain. A notably close contact interface, comprised of
extensive active site and exosite interactions, explains, in molecular detail,
the basis of the antithrombotic properties of therapeutic heparin.
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Selected figure(s)
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Figure 1.
Figure 1. Heparin catalysis of thrombin inhibition by
antithrombin. (a) The binding of the specific heparin
pentasaccharide to antithrombin induces a global conformational
change involving the expulsion of the hinge region (circled) of
the reactive center loop (RCL, yellow) from the central  -sheet
A (red), and extension (yellow) of the A and D helices (green
and cyan, respectively). The expulsion of the hinge region
increases the flexibility of the RCL and liberates the P1 Arg
(green ball-and-stick). The flexibility of the C-terminal
portion of the RCL (P' side) is limited, despite a three-residue
insertion (orange), owing to a tight hydrogen-bonded turn. (b)
Stereo representation of the crystal structure of the ternary
complex between antithrombin (colored as above), thrombin
(magenta) and heparin (ball-and-stick, with blue 2F[o] - F[c]
electron density contoured at 1  ).
Thrombin is docked toward the heparin-binding site of
antithrombin, and makes several exosite interactions. The
expulsion of the hinge region is not required to form this
complex, but the P' side of the RCL (orange) has been elongated.
(c) Density (calculated as in b) of the hinge region of
antithrombin in its complex with thrombin and heparin (yellow)
reveals the insertion of P15 Gly into -sheet
A, and a larger opening between strands 3 and 5A than seen for
pentasaccharide-bound antithrombin alone (gray). It has been
shown that high-affinity binding is not inconsistent with a
native-like hinge conformation, as demonstrated by the structure
in PDB entry 1NQ9 (ref. 42) (brown). (d) A comparison of the
conformations of the P' region of the RCL of pentasaccharide
activated antithrombin (gray) to that of antithrombin in the
complex with thrombin and heparin (yellow, oriented as in a and
b) reveals the requirement for P' elongation through the
breaking of hydrogen bonds.
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Figure 3.
Figure 3. Thrombin exosite interactions. (a,b) Thrombin
interacts closely with antithrombin by forming exosite
interactions in the  -loop
(a) and the Na^+-binding region (b) (colored as in Fig. 2a). (c)
The heparin mimetic (SR123781) used in crystallization is
labeled from A on the nonreducing end to P on the reducing end.
It is composed of a thrombin-binding site (ABC) and an
antithrombin-binding site (LMNOP). The interactions with
thrombin and antithrombin are indicated by lines, with solid
lines indicating a salt bridge, dashed lines hydrogen bonds,
dashed-dotted lines for water-mediated hydrogen bonds, and
dotted lines for potential interactions (only for Lys240).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2004,
11,
857-862)
copyright 2004.
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Figures were
selected
by the author.
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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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C.T.Esmon,
and
N.L.Esmon
(2011).
The link between vascular features and thrombosis.
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Annu Rev Physiol,
73,
503-514.
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A.Raghuraman,
P.D.Mosier,
and
U.R.Desai
(2010).
Understanding Dermatan Sulfate-Heparin Cofactor II Interaction through Virtual Library Screening.
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ACS Med Chem Lett,
1,
281-285.
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D.J.Johnson,
J.Langdown,
and
J.A.Huntington
(2010).
Molecular basis of factor IXa recognition by heparin-activated antithrombin revealed by a 1.7-A structure of the ternary complex.
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Proc Natl Acad Sci U S A,
107,
645-650.
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PDB code:
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J.A.Huntington,
and
J.C.Whisstock
(2010).
Molecular contortionism - on the physical limits of serpin 'loop-sheet' polymers.
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Biol Chem,
391,
973-982.
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J.Dong,
S.Yao,
X.Zhou,
L.Zhang,
and
Y.Xu
(2010).
Synthesis of N-heteroaroyl aminosaccharide derivatives as fibroblast growth factor 2 signaling modulators.
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Chem Pharm Bull (Tokyo),
58,
1210-1215.
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L.Muszbek,
Z.Bereczky,
B.Kovács,
and
I.Komáromi
(2010).
Antithrombin deficiency and its laboratory diagnosis.
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Clin Chem Lab Med,
48,
S67-S78.
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|
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M.Bekhouche,
D.Kronenberg,
S.Vadon-Le Goff,
C.Bijakowski,
N.H.Lim,
B.Font,
E.Kessler,
A.Colige,
H.Nagase,
G.Murphy,
D.J.Hulmes,
and
C.Moali
(2010).
Role of the netrin-like domain of procollagen C-proteinase enhancer-1 in the control of metalloproteinase activity.
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J Biol Chem,
285,
15950-15959.
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S.O.Dahms,
S.Hoefgen,
D.Roeser,
B.Schlott,
K.H.Gührs,
and
M.E.Than
(2010).
Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein.
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Proc Natl Acad Sci U S A,
107,
5381-5386.
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PDB code:
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W.J.Higgins,
D.M.Fox,
P.S.Kowalski,
J.E.Nielsen,
and
D.M.Worrall
(2010).
Heparin enhances serpin inhibition of the cysteine protease cathepsin L.
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J Biol Chem,
285,
3722-3729.
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A.Liang,
A.Raghuraman,
and
U.R.Desai
(2009).
Capillary electrophoretic study of small, highly sulfated, non-sugar molecules interacting with antithrombin.
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Electrophoresis,
30,
1544-1551.
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A.Raghuraman,
A.Liang,
C.Krishnasamy,
T.Lauck,
G.T.Gunnarsson,
and
U.R.Desai
(2009).
On designing non-saccharide, allosteric activators of antithrombin.
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Eur J Med Chem,
44,
2626-2631.
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J.Langdown,
K.J.Belzar,
W.J.Savory,
T.P.Baglin,
and
J.A.Huntington
(2009).
The critical role of hinge-region expulsion in the induced-fit heparin binding mechanism of antithrombin.
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J Mol Biol,
386,
1278-1289.
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PDB code:
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M.A.Frese,
F.Milz,
M.Dick,
W.C.Lamanna,
and
T.Dierks
(2009).
Characterization of the human sulfatase Sulf1 and its high affinity heparin/heparan sulfate interaction domain.
|
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J Biol Chem,
284,
28033-28044.
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P.G.Gettins,
and
S.T.Olson
(2009).
Exosite determinants of serpin specificity.
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J Biol Chem,
284,
20441-20445.
|
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P.P.Vicario,
Z.Lu,
I.Grigorian,
Z.Wang,
and
T.Schottman
(2009).
Cell adhesion and proliferation are reduced on stainless steel coated with polysaccharide-based polymeric formulations.
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J Biomed Mater Res B Appl Biomater,
89,
114-121.
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T.E.Adams,
W.Li,
and
J.A.Huntington
(2009).
Molecular basis of thrombomodulin activation of slow thrombin.
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J Thromb Haemost,
7,
1688-1695.
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PDB code:
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V.Chandrasekaran,
C.J.Lee,
P.Lin,
R.E.Duke,
and
L.G.Pedersen
(2009).
A computational modeling and molecular dynamics study of the Michaelis complex of human protein Z-dependent protease inhibitor (ZPI) and factor Xa (FXa).
|
| |
J Mol Model,
15,
897-911.
|
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|
|
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A.E.Schmidt,
M.F.Sun,
T.Ogawa,
S.P.Bajaj,
and
D.Gailani
(2008).
Functional role of residue 193 (chymotrypsin numbering) in serine proteases: influence of side chain length and beta-branching on the catalytic activity of blood coagulation factor XIa.
|
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Biochemistry,
47,
1326-1335.
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B.Richard,
R.Swanson,
S.Schedin-Weiss,
B.Ramirez,
G.Izaguirre,
P.G.Gettins,
and
S.T.Olson
(2008).
Characterization of the conformational alterations, reduced anticoagulant activity, and enhanced antiangiogenic activity of prelatent antithrombin.
|
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J Biol Chem,
283,
14417-14429.
|
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|
|
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|
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E.Di Cera
(2008).
Thrombin.
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Mol Aspects Med,
29,
203-254.
|
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K.Tan,
M.Duquette,
J.H.Liu,
K.Shanmugasundaram,
A.Joachimiak,
J.T.Gallagher,
A.C.Rigby,
J.H.Wang,
and
J.Lawler
(2008).
Heparin-induced cis- and trans-dimerization modes of the thrombospondin-1 N-terminal domain.
|
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J Biol Chem,
283,
3932-3941.
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PDB codes:
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M.Guerrini,
S.Guglieri,
B.Casu,
G.Torri,
P.Mourier,
C.Boudier,
and
C.Viskov
(2008).
Antithrombin-binding octasaccharides and role of extensions of the active pentasaccharide sequence in the specificity and strength of interaction. Evidence for very high affinity induced by an unusual glucuronic acid residue.
|
| |
J Biol Chem,
283,
26662-26675.
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M.Lafargue,
O.Joannes-Boyau,
P.M.Honoré,
B.Gauche,
H.Grand,
C.Fleureau,
H.Rozé,
and
G.Janvier
(2008).
Acquired deficit of antithrombin and role of supplementation in septic patients during continuous veno-venous hemofiltration.
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ASAIO J,
54,
124-128.
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|
|
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M.Lepretti,
S.Costantini,
G.Ammirato,
G.Giuberti,
M.Caraglia,
A.M.Facchiano,
S.Metafora,
and
P.Stiuso
(2008).
The N-terminal 1-16 peptide derived in vivo from protein seminal vesicle protein IV modulates alpha-thrombin activity: potential clinical implications.
|
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Exp Mol Med,
40,
541-549.
|
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N.S.Gandhi,
and
R.L.Mancera
(2008).
The structure of glycosaminoglycans and their interactions with proteins.
|
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Chem Biol Drug Des,
72,
455-482.
|
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|
|
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|
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S.B.Long,
M.B.Long,
R.R.White,
and
B.A.Sullenger
(2008).
Crystal structure of an RNA aptamer bound to thrombin.
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RNA,
14,
2504-2512.
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PDB code:
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T.H.Roberts,
and
J.Hejgaard
(2008).
Serpins in plants and green algae.
|
| |
Funct Integr Genomics,
8,
1.
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|
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W.Li,
and
J.A.Huntington
(2008).
The Heparin Binding Site of Protein C Inhibitor Is Protease-dependent.
|
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J Biol Chem,
283,
36039-36045.
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PDB code:
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W.Li,
T.E.Adams,
J.Nangalia,
C.T.Esmon,
and
J.A.Huntington
(2008).
Molecular basis of thrombin recognition by protein C inhibitor revealed by the 1.6-A structure of the heparin-bridged complex.
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Proc Natl Acad Sci U S A,
105,
4661-4666.
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PDB code:
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A.R.Bizzarri,
and
S.Cannistraro
(2007).
SERS detection of thrombin by protein recognition using functionalized gold nanoparticles.
|
| |
Nanomedicine,
3,
306-310.
|
|
|
|
|
|
|
C.Kannemeier,
A.Shibamiya,
F.Nakazawa,
H.Trusheim,
C.Ruppert,
P.Markart,
Y.Song,
E.Tzima,
E.Kennerknecht,
M.Niepmann,
M.L.von Bruehl,
D.Sedding,
S.Massberg,
A.Günther,
B.Engelmann,
and
K.T.Preissner
(2007).
Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation.
|
| |
Proc Natl Acad Sci U S A,
104,
6388-6393.
|
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|
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E.Di Cera,
M.J.Page,
A.Bah,
L.A.Bush-Pelc,
and
L.C.Garvey
(2007).
Thrombin allostery.
|
| |
Phys Chem Chem Phys,
9,
1291-1306.
|
|
|
|
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|
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E.Di Cera
(2007).
Thrombin as procoagulant and anticoagulant.
|
| |
J Thromb Haemost,
5,
196-202.
|
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|
|
|
|
|
G.Izaguirre,
R.Swanson,
S.M.Raja,
A.R.Rezaie,
and
S.T.Olson
(2007).
Mechanism by which exosites promote the inhibition of blood coagulation proteases by heparin-activated antithrombin.
|
| |
J Biol Chem,
282,
33609-33622.
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|
|
H.Yu,
and
X.Chen
(2007).
Carbohydrate post-glycosylational modifications.
|
| |
Org Biomol Chem,
5,
865-872.
|
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|
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J.Liu,
and
L.C.Pedersen
(2007).
Anticoagulant heparan sulfate: structural specificity and biosynthesis.
|
| |
Appl Microbiol Biotechnol,
74,
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|
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|
|
|
|
|
J.T.Crawley,
S.Zanardelli,
C.K.Chion,
and
D.A.Lane
(2007).
The central role of thrombin in hemostasis.
|
| |
J Thromb Haemost,
5,
95.
|
|
|
|
|
|
|
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F.Szlam,
H.Y.Sun,
T.Taketomi,
and
J.H.Levy
(2007).
Thrombin generation assay and viscoelastic coagulation monitors demonstrate differences in the mode of thrombin inhibition between unfractionated heparin and bivalirudin.
|
| |
Anesth Analg,
105,
933.
|
|
|
|
|
|
|
L.Beinrohr,
V.Harmat,
J.Dobó,
Z.Lörincz,
P.Gál,
and
P.Závodszky
(2007).
C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease.
|
| |
J Biol Chem,
282,
21100-21109.
|
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PDB code:
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|
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|
M.Kyotani,
K.Okumura,
A.Takagi,
T.Murate,
K.Yamamoto,
T.Matsushita,
M.Sugimura,
N.Kanayama,
T.Kobayashi,
H.Saito,
and
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(2007).
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|
| |
Am J Hematol,
82,
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|
|
|
|
|
|
|
P.C.Ong,
S.McGowan,
M.C.Pearce,
J.A.Irving,
W.T.Kan,
S.A.Grigoryev,
B.Turk,
G.A.Silverman,
K.Brix,
S.P.Bottomley,
J.C.Whisstock,
and
R.N.Pike
(2007).
DNA accelerates the inhibition of human cathepsin v by serpins.
|
| |
J Biol Chem,
282,
36980-36986.
|
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|
|
|
P.R.Gonzales,
T.D.Walston,
L.O.Camacho,
D.M.Kielar,
F.C.Church,
A.R.Rezaie,
and
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(2007).
Mutation of the H-helix in antithrombin decreases heparin stimulation of protease inhibition.
|
| |
Biochim Biophys Acta,
1774,
1431-1437.
|
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|
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|
|
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S.Glerup,
S.Kløverpris,
L.S.Laursen,
F.Dagnaes-Hansen,
S.Thiel,
C.A.Conover,
and
C.Oxvig
(2007).
Cell surface detachment of pregnancy-associated plasma protein-A requires the formation of intermolecular proteinase-inhibitor disulfide bonds and glycosaminoglycan covalently bound to the inhibitor.
|
| |
J Biol Chem,
282,
1769-1778.
|
|
|
|
|
|
|
T.Taketomi,
F.Szlam,
J.Vinten-Johansen,
J.H.Levy,
and
K.A.Tanaka
(2007).
Thrombin-activated thrombelastography for evaluation of thrombin interaction with thrombin inhibitors.
|
| |
Blood Coagul Fibrinolysis,
18,
761-767.
|
|
|
|
|
|
|
W.Li,
T.E.Adams,
M.Kjellberg,
J.Stenflo,
and
J.A.Huntington
(2007).
Structure of native protein C inhibitor provides insight into its multiple functions.
|
| |
J Biol Chem,
282,
13759-13768.
|
|
|
PDB codes:
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|
|
Y.M.Fortenberry,
H.C.Whinna,
S.T.Cooper,
T.Myles,
L.L.Leung,
and
F.C.Church
(2007).
Essential thrombin residues for inhibition by protein C inhibitor with the cofactors heparin and thrombomodulin.
|
| |
J Thromb Haemost,
5,
1486-1492.
|
|
|
|
|
|
|
Y.Wu,
C.Eigenbrot,
W.C.Liang,
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M.T.Lipari,
and
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(2007).
Structural insight into distinct mechanisms of protease inhibition by antibodies.
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| |
Proc Natl Acad Sci U S A,
104,
19784-19789.
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PDB codes:
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A.Beenken,
and
M.Mohammadi
(2006).
Hedgehogs like it sweet, too.
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Proc Natl Acad Sci U S A,
103,
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A.Dementiev,
J.Dobó,
and
P.G.Gettins
(2006).
Active site distortion is sufficient for proteinase inhibition by serpins: structure of the covalent complex of alpha1-proteinase inhibitor with porcine pancreatic elastase.
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| |
J Biol Chem,
281,
3452-3457.
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PDB code:
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A.Raghuraman,
P.D.Mosier,
and
U.R.Desai
(2006).
Finding a needle in a haystack: development of a combinatorial virtual screening approach for identifying high specificity heparin/heparan sulfate sequence(s).
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J Med Chem,
49,
3553-3562.
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D.J.Johnson,
J.Langdown,
W.Li,
S.A.Luis,
T.P.Baglin,
and
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(2006).
Crystal structure of monomeric native antithrombin reveals a novel reactive center loop conformation.
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| |
J Biol Chem,
281,
35478-35486.
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PDB codes:
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D.J.Johnson,
W.Li,
T.E.Adams,
and
J.A.Huntington
(2006).
Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation.
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| |
EMBO J,
25,
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PDB code:
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G.Izaguirre,
and
S.T.Olson
(2006).
Residues Tyr253 and Glu255 in strand 3 of beta-sheet C of antithrombin are key determinants of an exosite made accessible by heparin activation to promote rapid inhibition of factors Xa and IXa.
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| |
J Biol Chem,
281,
13424-13432.
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J.A.Huntington
(2006).
Shape-shifting serpins--advantages of a mobile mechanism.
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| |
Trends Biochem Sci,
31,
427-435.
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J.C.Whisstock,
and
S.P.Bottomley
(2006).
Molecular gymnastics: serpin structure, folding and misfolding.
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| |
Curr Opin Struct Biol,
16,
761-768.
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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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R.H.Law,
Q.Zhang,
S.McGowan,
A.M.Buckle,
G.A.Silverman,
W.Wong,
C.J.Rosado,
C.G.Langendorf,
R.N.Pike,
P.I.Bird,
and
J.C.Whisstock
(2006).
An overview of the serpin superfamily.
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| |
Genome Biol,
7,
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R.Sasisekharan,
R.Raman,
and
V.Prabhakar
(2006).
Glycomics approach to structure-function relationships of glycosaminoglycans.
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Annu Rev Biomed Eng,
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J.A.Huntington
(2005).
Molecular recognition mechanisms of thrombin.
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| |
J Thromb Haemost,
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J.C.Whisstock,
S.P.Bottomley,
P.I.Bird,
R.N.Pike,
and
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(2005).
Serpins 2005 - fun between the beta-sheets. Meeting report based upon presentations made at the 4th International Symposium on Serpin Structure, Function and Biology (Cairns, Australia).
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FEBS J,
272,
4868-4873.
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K.F.Fulton,
A.M.Buckle,
L.D.Cabrita,
J.A.Irving,
R.E.Butcher,
I.Smith,
S.Reeve,
A.M.Lesk,
S.P.Bottomley,
J.Rossjohn,
and
J.C.Whisstock
(2005).
The high resolution crystal structure of a native thermostable serpin reveals the complex mechanism underpinning the stressed to relaxed transition.
|
| |
J Biol Chem,
280,
8435-8442.
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PDB code:
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K.Ingold,
A.Zumsteg,
A.Tardivel,
B.Huard,
Q.G.Steiner,
T.G.Cachero,
F.Qiang,
L.Gorelik,
S.L.Kalled,
H.Acha-Orbea,
P.D.Rennert,
J.Tschopp,
and
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(2005).
Identification of proteoglycans as the APRIL-specific binding partners.
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| |
J Exp Med,
201,
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M.de Kort,
R.C.Buijsman,
and
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(2005).
Synthetic heparin derivatives as new anticoagulant drugs.
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| |
Drug Discov Today,
10,
769-779.
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R.N.Pike,
A.M.Buckle,
B.F.le Bonniec,
and
F.C.Church
(2005).
Control of the coagulation system by serpins. Getting by with a little help from glycosaminoglycans.
|
| |
FEBS J,
272,
4842-4851.
|
|
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W.Bode
(2005).
The structure of thrombin, a chameleon-like proteinase.
|
| |
J Thromb Haemost,
3,
2379-2388.
|
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|
W.J.Carter,
E.Cama,
and
J.A.Huntington
(2005).
Crystal structure of thrombin bound to heparin.
|
| |
J Biol Chem,
280,
2745-2749.
|
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PDB code:
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J.Langdown,
D.J.Johnson,
T.P.Baglin,
and
J.A.Huntington
(2004).
Allosteric activation of antithrombin critically depends upon hinge region extension.
|
| |
J Biol Chem,
279,
47288-47297.
|
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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
code is
shown on the right.
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