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PDBsum entry 1qf0
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.24.27
- thermolysin.
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Reaction:
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Preferential cleavage: Xaa-|-Leu > Xaa-|-Phe.
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Cofactor:
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Ca(2+); Zn(2+)
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DOI no:
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Biochemistry
38:12569-12576
(1999)
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PubMed id:
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Crystal structures of alpha-mercaptoacyldipeptides in the thermolysin active site: structural parameters for a Zn monodentation or bidentation in metalloendopeptidases.
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J.F.Gaucher,
M.Selkti,
G.Tiraboschi,
T.Prangé,
B.P.Roques,
A.Tomas,
M.C.Fournié-Zaluski.
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ABSTRACT
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Three alpha-mercaptoacyldipeptides differing essentially in the size of their
C-terminal residues have been crystallized in the thermolysin active site. A new
mode of binding was observed for 3 [HS-CH(CH(2)Ph)CO-Phe-Tyr] and 4
[HS-CH((CH(2))(4)CH(3))CO-Phe-Ala], in which the mercaptoacyl moieties act as
bidentates with Zn-S and Zn-O distances of 2.3 and 2.4 A, respectively, the side
chains fitting the S(1), S(1)', and S(2)' pockets. Moreover, a distance of 3.1 A
between the sulfur atom and the OE1 of Glu(143) suggests that they are H-bonded
and that one of these atoms is protonated. This H-bond network involving
Glu(143), the mercaptoacyl group of the inhibitor, and the Zn ion could be
considered a "modified" transition state mimic of the peptide bond hydrolysis.
Due to the presence of the hindering (5-phenyl)proline, the inhibitor
HS-CH(CH(2)Ph)CO-Gly-(5-Ph)Pro (2) interacts through the usual Zn monodentation
via the thiol group and occupancy of S(1)' and S(2)' subsites by the aromatic
moieties, the proline ring being outside the active site. The inhibitory
potencies are consistent with these structural data, with higher affinities for
3 (4.2 x 10(-)(8) M) and 4 (4.8 x 10(-)(8) M) than for 2 (1.2 x 10(-)(6) M). The
extension of the results, obtained with thermolysin being considered as the
model of physiological zinc metallopeptidases, allows inhibitor-recognition
modes for other peptidases, such as angiotensin converting enzyme and neutral
endopeptidase, to be proposed and opens interesting possibilities for the design
of new classes of inhibitors.
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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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S.Kostenko,
M.T.Khan,
I.Sylte,
and
U.Moens
(2011).
The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor.
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Cell Mol Life Sci,
68,
289-301.
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L.Hocharoen,
and
J.A.Cowan
(2009).
Metallotherapeutics: novel strategies in drug design.
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Chemistry,
15,
8670-8676.
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O.A.Adekoya,
and
I.Sylte
(2009).
The thermolysin family (m4) of enzymes: therapeutic and biotechnological potential.
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Chem Biol Drug Des,
73,
7.
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Y.Z.Zhang,
S.F.Zhu,
Y.Cai,
H.X.Mao,
and
Q.L.Zhou
(2009).
Copper-catalyzed enantioselective carbenoid insertion into S-H bonds.
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Chem Commun (Camb),
(),
5362-5364.
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B.Seebeck,
I.Reulecke,
A.Kämper,
and
M.Rarey
(2008).
Modeling of metal interaction geometries for protein-ligand docking.
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Proteins,
71,
1237-1254.
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G.Lutfullah,
F.Amin,
Z.Khan,
N.Azhar,
M.K.Azim,
S.Noor,
and
K.Shoukat
(2008).
Homology modeling of hemagglutinin/protease [HA/P (vibriolysin)] from Vibrio cholerae: sequence comparision, residue interactions and molecular mechanism.
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Protein J,
27,
105-114.
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C.Oefner,
S.Pierau,
H.Schulz,
and
G.E.Dale
(2007).
Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.
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Acta Crystallogr D Biol Crystallogr,
63,
975-981.
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PDB code:
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N.H.Gokhale,
S.Bradford,
and
J.A.Cowan
(2007).
Stimulation and oxidative catalytic inactivation of thermolysin by copper.Cys-Gly-His-Lys.
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J Biol Inorg Chem,
12,
981-987.
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B.E.Turk,
T.Y.Wong,
R.Schwarzenbacher,
E.T.Jarrell,
S.H.Leppla,
R.J.Collier,
R.C.Liddington,
and
L.C.Cantley
(2004).
The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor.
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Nat Struct Mol Biol,
11,
60-66.
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PDB codes:
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M.Selkti,
A.Tomas,
J.F.Gaucher,
T.Prangé,
M.C.Fournié-Zaluski,
H.Chen,
and
B.P.Roques
(2003).
Interactions of a new alpha-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition.
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Acta Crystallogr D Biol Crystallogr,
59,
1200-1205.
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PDB codes:
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A.de Kreij,
B.van den Burg,
G.Venema,
G.Vriend,
V.G.Eijsink,
and
J.E.Nielsen
(2002).
The effects of modifying the surface charge on the catalytic activity of a thermolysin-like protease.
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J Biol Chem,
277,
15432-15438.
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J.Antony,
N.Gresh,
L.Olsen,
L.Hemmingsen,
C.J.Schofield,
and
R.Bauer
(2002).
Binding of D- and L-captopril inhibitors to metallo-beta-lactamase studied by polarizable molecular mechanics and quantum mechanics.
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J Comput Chem,
23,
1281-1296.
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J.F.Gaucher,
M.Selkti,
T.Prangé,
and
A.Tomas
(2002).
The 2.2 A resolution structure of thermolysin (TLN) crystallized in the presence of potassium thiocyanate.
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Acta Crystallogr D Biol Crystallogr,
58,
2198-2200.
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PDB code:
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M.M.Bernardo,
S.Brown,
Z.H.Li,
R.Fridman,
and
S.Mobashery
(2002).
Design, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinases.
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J Biol Chem,
277,
11201-11207.
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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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Links
