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* Residue conservation analysis
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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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J Med Chem
42:1376-1383
(1999)
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PubMed id:
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Bound structures of novel P3-P1' beta-strand mimetic inhibitors of thrombin.
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R.St Charles,
J.H.Matthews,
E.Zhang,
A.Tulinsky.
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ABSTRACT
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The X-ray crystal structures of four beta-strand-templated active site
inhibitors of thrombin containing P1' groups have been determined and refined at
about 2.1-A resolution to crystallographic R-values between 0.148 and 0.164. Two
of the inhibitors have an alpha-ketoamide functionality at the scissile bond;
the other two have a nonhydrolyzable electrophilic group at the P1' position.
The binding of lysine is compared with that of arginine at the S1 specificity
site, while that of D,L-phenylalanine enantiomorphs is compared in the S3 region
of thrombin. Four different P1' moieties bind at the S1' subsite in three
different ways. The binding constants vary between 2.0 microM and 70 pM. The
bound structures are used to intercorrelate the various binding constants and
also lead to insightful inferences concerning binding at the S1' site of
thrombin.
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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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X.Jian,
M.Cavenagh,
J.M.Gruschus,
P.A.Randazzo,
and
R.A.Kahn
(2010).
Modifications to the C-terminus of Arf1 alter cell functions and protein interactions.
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Traffic,
11,
732-742.
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K.Ede,
K.K.Hwang,
C.C.Wu,
M.Wu,
Y.H.Yang,
W.S.Lin,
D.Chien,
P.C.Chen,
B.P.Tsao,
D.K.McCurdy,
and
P.P.Chen
(2009).
Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice.
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Arthritis Rheum,
60,
3108-3117.
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M.I.Zavodszky,
A.Rohatgi,
J.R.Van Voorst,
H.Yan,
and
L.A.Kuhn
(2009).
Scoring ligand similarity in structure-based virtual screening.
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J Mol Recognit,
22,
280-292.
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W.S.Lin,
P.C.Chen,
C.D.Yang,
E.Cho,
B.H.Hahn,
J.Grossman,
K.K.Hwang,
and
P.P.Chen
(2007).
Some antiphospholipid antibodies recognize conformational epitopes shared by beta2-glycoprotein I and the homologous catalytic domains of several serine proteases.
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Arthritis Rheum,
56,
1638-1647.
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B.A.Malcolm,
R.Liu,
F.Lahser,
S.Agrawal,
B.Belanger,
N.Butkiewicz,
R.Chase,
F.Gheyas,
A.Hart,
D.Hesk,
P.Ingravallo,
C.Jiang,
R.Kong,
J.Lu,
J.Pichardo,
A.Prongay,
A.Skelton,
X.Tong,
S.Venkatraman,
E.Xia,
V.Girijavallabhan,
and
F.G.Njoroge
(2006).
SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells.
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Antimicrob Agents Chemother,
50,
1013-1020.
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G.A.Landrum,
J.E.Penzotti,
and
S.Putta
(2006).
Feature-map vectors: a new class of informative descriptors for computational drug discovery.
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J Comput Aided Mol Des,
20,
751-762.
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Y.H.Yang,
K.K.Hwang,
J.FitzGerald,
J.M.Grossman,
M.Taylor,
B.H.Hahn,
and
P.P.Chen
(2006).
Antibodies against the activated coagulation factor X (FXa) in the antiphospholipid syndrome that interfere with the FXa inactivation by antithrombin.
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J Immunol,
177,
8219-8225.
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C.S.Lu,
A.A.Horizon,
K.K.Hwang,
J.FitzGerald,
W.S.Lin,
B.H.Hahn,
D.J.Wallace,
A.L.Metzger,
M.H.Weisman,
and
P.P.Chen
(2005).
Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome.
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Arthritis Rheum,
52,
4018-4027.
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J.Cluzeau,
and
W.D.Lubell
(2005).
Design, synthesis, and application of azabicyclo[X.Y.0]alkanone amino acids as constrained dipeptide surrogates and peptide mimics.
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Biopolymers,
80,
98.
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M.I.Zavodszky,
and
L.A.Kuhn
(2005).
Side-chain flexibility in protein-ligand binding: the minimal rotation hypothesis.
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Protein Sci,
14,
1104-1114.
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K.K.Hwang,
C.D.Yang,
W.Yan,
J.M.Grossman,
B.H.Hahn,
and
P.P.Chen
(2003).
A thrombin-cross-reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C.
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Arthritis Rheum,
48,
1622-1630.
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J.Cacciola,
J.M.Fevig,
P.F.Stouten,
R.S.Alexander,
R.M.Knabb,
and
R.R.Wexler
(2000).
Synthesis and activity studies of conformationally restricted alpha-ketoamide factor Xa inhibitors.
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Bioorg Med Chem Lett,
10,
1253-1256.
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J.J.Slon-Usakiewicz,
J.Sivaraman,
Y.Li,
M.Cygler,
and
Y.Konishi
(2000).
Design of P1' and P3' residues of trivalent thrombin inhibitors and their crystal structures.
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Biochemistry,
39,
2384-2391.
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PDB codes:
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K.Kahn,
and
T.C.Bruice
(2000).
Alpha-ketoamides and alpha-ketocarbonyls: conformational analysis and development of all-atom OPLS force field.
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Bioorg Med Chem,
8,
1881-1891.
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R.Krishnan,
I.Mochalkin,
R.Arni,
and
A.Tulinsky
(2000).
Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1.
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Acta Crystallogr D Biol Crystallogr,
56,
294-303.
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PDB codes:
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R.Recacha,
M.J.Costanzo,
B.E.Maryanoff,
M.Carson,
L.DeLucas,
and
D.Chattopadhyay
(2000).
Structure of human alpha-thrombin complexed with RWJ-51438 at 1.7 A: unusual perturbation of the 60A-60I insertion loop.
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Acta Crystallogr D Biol Crystallogr,
56,
1395-1400.
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PDB code:
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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
