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PDBsum entry 1t32
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References listed in PDB file
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Key reference
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Title
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A novel, Potent dual inhibitor of the leukocyte proteases cathepsin g and chymase: molecular mechanisms and anti-Inflammatory activity in vivo.
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Authors
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L.De garavilla,
M.N.Greco,
N.Sukumar,
Z.W.Chen,
A.O.Pineda,
F.S.Mathews,
E.Di cera,
E.C.Giardino,
G.I.Wells,
B.J.Haertlein,
J.A.Kauffman,
T.W.Corcoran,
C.K.Derian,
A.J.Eckardt,
B.P.Damiano,
P.Andrade-Gordon,
B.E.Maryanoff.
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Ref.
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J Biol Chem, 2005,
280,
18001-18007.
[DOI no: ]
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PubMed id
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Abstract
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Certain leukocytes release serine proteases that sustain inflammatory processes
and cause disease conditions, such as asthma and chronic obstructive pulmonary
disease. We identified beta-ketophosphonate 1 (JNJ-10311795; RWJ-355871) as a
novel, potent dual inhibitor of neutrophil cathepsin G (K(i) = 38 nm) and mast
cell chymase (K(i) = 2.3 nm). The x-ray crystal structures of 1 complexed with
human cathepsin G (1.85 A) and human chymase (1.90 A) reveal the molecular basis
of the dual inhibition. Ligand 1 occupies the S(1) and S(2) subsites of
cathepsin G and chymase similarly, with the 2-naphthyl in S(1), the 1-naphthyl
in S(2), and the phosphonate group in a complex network of hydrogen bonds.
Surprisingly, however, the carboxamido-N-(naphthalene-2-carboxyl)piperidine
group is found to bind in two distinct conformations. In cathepsin G, this group
occupies the hydrophobic S(3)/S(4) subsites, whereas in chymase, it does not;
rather, it folds onto the 1-naphthyl group of the inhibitor itself. Compound 1
exhibited noteworthy anti-inflammatory activity in rats for glycogen-induced
peritonitis and lipopolysaccharide-induced airway inflammation. In addition to a
marked reduction in neutrophil influx, 1 reversed increases in inflammatory
mediators interleukin-1alpha, interleukin-1beta, tissue necrosis factor-alpha,
and monocyte chemotactic protein-1 in the glycogen model and reversed increases
in airway nitric oxide levels in the lipopolysaccharide model. These findings
demonstrate that it is possible to inhibit both cathepsin G and chymase with a
single molecule and suggest an exciting opportunity in the treatment of asthma
and chronic obstructive pulmonary disease.
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Figure 2.
FIG. 2. X-ray crystallographic results. A, a view of the
x-ray structure of 1 (yellow, with standard coloring for oxygen
and nitrogen atoms) in the active site of Cat G, represented as
a Connolly surface (green), at 1.85 Å resolution. B, a
view of the x-ray structure of 1 (yellow, with standard coloring
for oxygen and nitrogen atoms) in the active site of chymase,
represented as a Connolly surface (green), at 1.9 Å
resolution. C, a schematic representation of the interactions
surrounding the S[1] and S[2] subsites for 1·Cat G. D, a
schematic representation of the interactions surrounding the
S[1] and S[2] subsites for 1·chymase. For A and B,
certain amino acid residues and enzyme subsites are labeled. For
C and D, ligand 1 is shown in its approximate orientation in
each complex, with the amide bond that rotates  180°
highlighted in red. The hydrogen bonds are depicted by dashed
lines accompanied by the distances between the heavy atoms.
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Figure 5.
FIG. 5. Inhibition of LPS-induced neutrophilia in the lungs
of rats. Data are given for counts of white blood cells: total
white blood cells (Total WBC), neutrophils (NEUT), lymphocytes
(LYMPH), monocytes (MONO), eosinophils (EOS), and basophils
(BASO). Each set of three clustered bars represents, from left
to right, saline control (white), LPS treatment (black), and
treatment with LPS + 1 (gray). The inset graph shows an
expansion of the cell counts for monocytes, eosinophils, and
basophils. Data are reported as mean ± S.E.; an asterisk
indicates statistical significance at p  0.01 relative to the
vehicle-treated LPS group (black bars).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
18001-18007)
copyright 2005.
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Secondary reference #1
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Title
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The 1.8 a crystal structure of human cathepsin g in complex with suc-Val-Pro-Phep-(Oph)2: a janus-Faced proteinase with two opposite specificities.
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Authors
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P.Hof,
I.Mayr,
R.Huber,
E.Korzus,
J.Potempa,
J.Travis,
J.C.Powers,
W.Bode.
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Ref.
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Embo J, 1996,
15,
5481-5491.
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PubMed id
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