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* Residue conservation analysis
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Nat Struct Biol
1:48-54
(1994)
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PubMed id:
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The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions.
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H.A.Schreuder,
B.de Boer,
R.Dijkema,
J.Mulders,
H.J.Theunissen,
P.D.Grootenhuis,
W.G.Hol.
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ABSTRACT
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Antithrombin is a member of the serine proteinase inhibitor (serpin) family
which contain a flexible reactive site loop that interacts with, and is cleaved
by the target proteinase. In cleaved and latent serpins, the reactive site loop
is inserted into a large central beta-sheet in the same molecule, whereas in
ovalbumin, a nonfunctional serpin, the reactive site loop is completely exposed
and in an alpha-helical conformation. However, in neither conformation can the
reactive site loop bind to target proteinases. Here we report the structure of
an intact and cleaved human antithrombin complex. The intact reactive site loop
is in a novel conformation that seems well suited for interaction with
proteinases such as thrombin and blood coagulation factor Xa.
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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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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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L.Muszbek,
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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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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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D.J.Johnson,
J.Langdown,
W.Li,
S.A.Luis,
T.P.Baglin,
and
J.A.Huntington
(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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J.Pilch,
C.M.Franzin,
L.M.Knowles,
F.J.Ferrer,
F.M.Marassi,
and
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(2006).
The anti-angiogenic peptide anginex disrupts the cell membrane.
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J Mol Biol,
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M.Kjellberg,
T.Ikonomou,
and
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(2006).
The cleaved and latent forms of antithrombin are normal constituents of blood plasma: a quantitative method to measure cleaved antithrombin.
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J Thromb Haemost,
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J.Hejgaard
(2005).
Inhibitory plant serpins with a sequence of three glutamine residues in the reactive center.
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Biol Chem,
386,
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A.Dementiev,
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J.M.Herbert,
and
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(2004).
The ternary complex of antithrombin-anhydrothrombin-heparin reveals the basis of inhibitor specificity.
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Nat Struct Mol Biol,
11,
863-867.
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PDB code:
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D.J.Johnson,
and
J.A.Huntington
(2004).
The influence of hinge region residue Glu-381 on antithrombin allostery and metastability.
|
| |
J Biol Chem,
279,
4913-4921.
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PDB code:
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D.O'Keeffe,
S.T.Olson,
N.Gasiunas,
J.Gallagher,
T.P.Baglin,
and
J.A.Huntington
(2004).
The heparin binding properties of heparin cofactor II suggest an antithrombin-like activation mechanism.
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J Biol Chem,
279,
50267-50273.
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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.
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J Biol Chem,
279,
47288-47297.
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S.Janciauskiene,
S.Eriksson,
F.Callea,
M.Mallya,
A.Zhou,
K.Seyama,
S.Hata,
and
D.A.Lomas
(2004).
Differential detection of PAS-positive inclusions formed by the Z, Siiyama, and Mmalton variants of alpha1-antitrypsin.
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Hepatology,
40,
1203-1210.
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U.R.Desai
(2004).
New antithrombin-based anticoagulants.
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Med Res Rev,
24,
151-181.
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A.Dementiev,
M.Simonovic,
K.Volz,
and
P.G.Gettins
(2003).
Canonical inhibitor-like interactions explain reactivity of alpha1-proteinase inhibitor Pittsburgh and antithrombin with proteinases.
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J Biol Chem,
278,
37881-37887.
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PDB codes:
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A.Zhou,
P.E.Stein,
J.A.Huntington,
and
R.W.Carrell
(2003).
Serpin polymerization is prevented by a hydrogen bond network that is centered on his-334 and stabilized by glycerol.
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J Biol Chem,
278,
15116-15122.
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PDB code:
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B.De Taeye,
G.Compernolle,
M.Dewilde,
W.Biesemans,
and
P.J.Declerck
(2003).
Immobilization of the distal hinge in the labile serpin plasminogen activator inhibitor 1: identification of a transition state with distinct conformational and functional properties.
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J Biol Chem,
278,
23899-23905.
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E.Marszal,
D.Danino,
and
A.Shrake
(2003).
A novel mode of polymerization of alpha1-proteinase inhibitor.
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J Biol Chem,
278,
19611-19618.
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G.L.Long,
M.Kjellberg,
B.O.Villoutreix,
and
J.Stenflo
(2003).
Probing plasma clearance of the thrombin-antithrombin complex with a monoclonal antibody against the putative serpin-enzyme complex receptor-binding site.
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Eur J Biochem,
270,
4059-4069.
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J.A.Huntington
(2003).
Mechanisms of glycosaminoglycan activation of the serpins in hemostasis.
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J Thromb Haemost,
1,
1535-1549.
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N.V.Gorlatova,
H.Elokdah,
K.Fan,
D.L.Crandall,
and
D.A.Lawrence
(2003).
Mapping of a conformational epitope on plasminogen activator inhibitor-1 by random mutagenesis. Implications for serpin function.
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J Biol Chem,
278,
16329-16335.
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B.N.Terp,
D.N.Cooper,
I.T.Christensen,
F.S.Jørgensen,
P.Bross,
N.Gregersen,
and
M.Krawczak
(2002).
Assessing the relative importance of the biophysical properties of amino acid substitutions associated with human genetic disease.
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Hum Mutat,
20,
98.
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K.J.Belzar,
A.Zhou,
R.W.Carrell,
P.G.Gettins,
and
J.A.Huntington
(2002).
Helix D elongation and allosteric activation of antithrombin.
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J Biol Chem,
277,
8551-8558.
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M.P.McGee,
J.Liang,
and
J.Luba
(2002).
Hydration effects of heparin on antithrombin probed by osmotic stress.
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Biophys J,
82,
1040-1049.
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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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R.Geiben-Lynn,
N.Brown,
B.D.Walker,
and
A.D.Luster
(2002).
Purification of a modified form of bovine antithrombin III as an HIV-1 CD8+ T-cell antiviral factor.
|
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J Biol Chem,
277,
42352-42357.
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T.P.Baglin,
R.W.Carrell,
F.C.Church,
C.T.Esmon,
and
J.A.Huntington
(2002).
Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism.
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Proc Natl Acad Sci U S A,
99,
11079-11084.
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PDB codes:
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J.P.Ludeman,
J.C.Whisstock,
P.C.Hopkins,
B.F.Le Bonniec,
and
S.P.Bottomley
(2001).
Structure of a serpin-enzyme complex probed by cysteine substitutions and fluorescence spectroscopy.
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Biophys J,
80,
491-497.
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L.Jankova,
S.J.Harrop,
D.N.Saunders,
J.L.Andrews,
K.C.Bertram,
A.R.Gould,
M.S.Baker,
and
P.M.Curmi
(2001).
Crystal structure of the complex of plasminogen activator inhibitor 2 with a peptide mimicking the reactive center loop.
|
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J Biol Chem,
276,
43374-43382.
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PDB code:
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S.Michel,
J.P.Charrier,
G.Deleage,
N.Battail-Poirot,
M.Jolivet,
and
C.Jolivet-Reynaud
(2001).
Analysis of prostate specific antigen and alpha1-antichymotrypsin interaction using antipeptide monoclonal antibodies.
|
| |
J Urol,
165,
301-306.
|
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S.P.Bottomley,
I.D.Lawrenson,
D.Tew,
W.Dai,
J.C.Whisstock,
and
R.N.Pike
(2001).
The role of strand 1 of the C beta-sheet in the structure and function of alpha(1)-antitrypsin.
|
| |
Protein Sci,
10,
2518-2524.
|
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A.Futamura,
and
P.G.Gettins
(2000).
Serine 380 (P14) --> glutamate mutation activates antithrombin as an inhibitor of factor Xa.
|
| |
J Biol Chem,
275,
4092-4098.
|
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C.Green,
E.Levashina,
C.McKimmie,
T.Dafforn,
J.M.Reichhart,
and
D.Gubb
(2000).
The necrotic gene in Drosophila corresponds to one of a cluster of three serpin transcripts mapping at 43A1.2.
|
| |
Genetics,
156,
1117-1127.
|
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D.A.Lawrence,
S.T.Olson,
S.Muhammad,
D.E.Day,
J.O.Kvassman,
D.Ginsburg,
and
J.D.Shore
(2000).
Partitioning of serpin-proteinase reactions between stable inhibition and substrate cleavage is regulated by the rate of serpin reactive center loop insertion into beta-sheet A.
|
| |
J Biol Chem,
275,
5839-5844.
|
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J.L.Meagher,
S.T.Olson,
and
P.G.Gettins
(2000).
Critical role of the linker region between helix D and strand 2A in heparin activation of antithrombin.
|
| |
J Biol Chem,
275,
2698-2704.
|
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K.Strandberg,
M.Kjellberg,
E.M.Erb,
U.Persson,
D.F.Mosher,
B.O.Villoutreix,
and
J.Stenflo
(2000).
Activated protein C-protein C inhibitor complex formation: characterization of a neoepitope provides evidence for extensive insertion of the reactive center loop.
|
| |
Biochemistry,
39,
15713-15720.
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P.R.Elliott,
X.Y.Pei,
T.R.Dafforn,
and
D.A.Lomas
(2000).
Topography of a 2.0 A structure of alpha1-antitrypsin reveals targets for rational drug design to prevent conformational disease.
|
| |
Protein Sci,
9,
1274-1281.
|
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PDB code:
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A.J.Fisher,
W.Cruz,
S.J.Zoog,
C.L.Schneider,
and
P.D.Friesen
(1999).
Crystal structure of baculovirus P35: role of a novel reactive site loop in apoptotic caspase inhibition.
|
| |
EMBO J,
18,
2031-2039.
|
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PDB code:
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A.Lombardi,
G.De Simone,
S.Galdiero,
N.Staiano,
F.Nastri,
and
V.Pavone
(1999).
From natural to synthetic multisite thrombin inhibitors.
|
| |
Biopolymers,
51,
19-39.
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A.M.Sharp,
P.E.Stein,
N.S.Pannu,
R.W.Carrell,
M.B.Berkenpas,
D.Ginsburg,
D.A.Lawrence,
and
R.J.Read
(1999).
The active conformation of plasminogen activator inhibitor 1, a target for drugs to control fibrinolysis and cell adhesion.
|
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Structure,
7,
111-118.
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PDB code:
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H.Im,
E.J.Seo,
and
M.H.Yu
(1999).
Metastability in the inhibitory mechanism of human alpha1-antitrypsin.
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J Biol Chem,
274,
11072-11077.
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J.A.Hirsch,
C.Schubert,
V.V.Gurevich,
and
P.B.Sigler
(1999).
The 2.8 A crystal structure of visual arrestin: a model for arrestin's regulation.
|
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Cell,
97,
257-269.
|
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PDB code:
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J.Li,
Z.Wang,
B.Canagarajah,
H.Jiang,
M.Kanost,
and
E.J.Goldsmith
(1999).
The structure of active serpin 1K from Manduca sexta.
|
| |
Structure,
7,
103-109.
|
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PDB code:
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M.S.O'Reilly,
S.Pirie-Shepherd,
W.S.Lane,
and
J.Folkman
(1999).
Antiangiogenic activity of the cleaved conformation of the serpin antithrombin.
|
| |
Science,
285,
1926-1928.
|
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S.J.Harrop,
L.Jankova,
M.Coles,
D.Jardine,
J.S.Whittaker,
A.R.Gould,
A.Meister,
G.C.King,
B.C.Mabbutt,
and
P.M.Curmi
(1999).
The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function.
|
| |
Structure,
7,
43-54.
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PDB code:
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S.M.Van Patten,
E.Hanson,
R.Bernasconi,
K.Zhang,
P.Manavalan,
E.S.Cole,
J.M.McPherson,
and
T.Edmunds
(1999).
Oxidation of methionine residues in antithrombin. Effects on biological activity and heparin binding.
|
| |
J Biol Chem,
274,
10268-10276.
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T.R.Dafforn,
R.Mahadeva,
P.R.Elliott,
P.Sivasothy,
and
D.A.Lomas
(1999).
A kinetic mechanism for the polymerization of alpha1-antitrypsin.
|
| |
J Biol Chem,
274,
9548-9555.
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V.Picard,
P.E.Marque,
F.Paolucci,
M.Aiach,
and
B.F.Le Bonniec
(1999).
Topology of the stable serpin-protease complexes revealed by an autoantibody that fails to react with the monomeric conformers of antithrombin.
|
| |
J Biol Chem,
274,
4586-4593.
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C.M.Lukacs,
H.Rubin,
and
D.W.Christianson
(1998).
Engineering an anion-binding cavity in antichymotrypsin modulates the "spring-loaded" serpin-protease interaction.
|
| |
Biochemistry,
37,
3297-3304.
|
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PDB codes:
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H.L.Fitton,
R.Skinner,
T.R.Dafforn,
L.Jin,
and
R.N.Pike
(1998).
The N-terminal segment of antithrombin acts as a steric gate for the binding of heparin.
|
| |
Protein Sci,
7,
782-788.
|
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J.L.Meagher,
J.M.Beechem,
S.T.Olson,
and
P.G.Gettins
(1998).
Deconvolution of the fluorescence emission spectrum of human antithrombin and identification of the tryptophan residues that are responsive to heparin binding.
|
| |
J Biol Chem,
273,
23283-23289.
|
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J.Liang,
and
M.P.McGee
(1998).
Hydration structure of antithrombin conformers and water transfer during reactive loop insertion.
|
| |
Biophys J,
75,
573-582.
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J.Whisstock,
R.Skinner,
and
A.M.Lesk
(1998).
An atlas of serpin conformations.
|
| |
Trends Biochem Sci,
23,
63-67.
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K.N.Lee,
H.Im,
S.W.Kang,
and
M.H.Yu
(1998).
Characterization of a human alpha1-antitrypsin variant that is as stable as ovalbumin.
|
| |
J Biol Chem,
273,
2509-2516.
|
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R.Mahadeva,
and
D.A.Lomas
(1998).
Genetics and respiratory disease. 2. Alpha 1-antitrypsin deficiency, cirrhosis and emphysema.
|
| |
Thorax,
53,
501-505.
|
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R.W.Carrell,
and
B.Gooptu
(1998).
Conformational changes and disease--serpins, prions and Alzheimer's.
|
| |
Curr Opin Struct Biol,
8,
799-809.
|
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Y.Xue,
P.Björquist,
T.Inghardt,
M.Linschoten,
D.Musil,
L.Sjölin,
and
J.Deinum
(1998).
Interfering with the inhibitory mechanism of serpins: crystal structure of a complex formed between cleaved plasminogen activator inhibitor type 1 and a reactive-centre loop peptide.
|
| |
Structure,
6,
627-636.
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PDB code:
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H.L.Fitton,
R.N.Pike,
R.W.Carrell,
and
W.S.Chang
(1997).
Mechanisms of antithrombin polymerisation and heparin activation probed by the insertion of synthetic reactive loop peptides.
|
| |
Biol Chem,
378,
1059-1063.
|
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|
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L.Jin,
J.P.Abrahams,
R.Skinner,
M.Petitou,
R.N.Pike,
and
R.W.Carrell
(1997).
The anticoagulant activation of antithrombin by heparin.
|
| |
Proc Natl Acad Sci U S A,
94,
14683-14688.
|
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PDB code:
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M.R.Wardell,
W.S.Chang,
D.Bruce,
R.Skinner,
A.M.Lesk,
and
R.W.Carrell
(1997).
Preparative induction and characterization of L-antithrombin: a structural homologue of latent plasminogen activator inhibitor-1.
|
| |
Biochemistry,
36,
13133-13142.
|
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|
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P.E.Bock,
S.T.Olson,
and
I.Björk
(1997).
Inactivation of thrombin by antithrombin is accompanied by inactivation of regulatory exosite I.
|
| |
J Biol Chem,
272,
19837-19845.
|
|
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|
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|
|
R.Egelund,
S.L.Schousboe,
L.Sottrup-Jensen,
K.W.Rodenburg,
and
P.A.Andreasen
(1997).
Type-1 plasminogen-activator inhibitor -- conformational differences between latent, active, reactive-centre-cleaved and plasminogen-activator-complexed forms, as probed by proteolytic susceptibility.
|
| |
Eur J Biochem,
248,
775-785.
|
|
|
|
|
|
|
R.N.Pike,
J.Potempa,
R.Skinner,
H.L.Fitton,
W.T.McGraw,
J.Travis,
M.Owen,
L.Jin,
and
R.W.Carrell
(1997).
Heparin-dependent modification of the reactive center arginine of antithrombin and consequent increase in heparin binding affinity.
|
| |
J Biol Chem,
272,
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PDB code:
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PDB code:
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|
|
|
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