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PDBsum entry 1c2m
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Hydrolase/hydrolase inhibitor
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PDB id
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1c2m
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Design of potent selective zinc-Mediated serine protease inhibitors.
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Authors
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B.A.Katz,
J.M.Clark,
J.S.Finer-Moore,
T.E.Jenkins,
C.R.Johnson,
M.J.Ross,
C.Luong,
W.R.Moore,
R.M.Stroud.
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Ref.
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Nature, 1998,
391,
608-612.
[DOI no: ]
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PubMed id
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Abstract
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Many serine proteases are targets for therapeutic intervention because they
often play key roles in disease. Small molecule inhibitors of serine proteases
with high affinity are especially interesting as they could be used as scaffolds
from which to develop drugs selective for protease targets. One such inhibitor
is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best
inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively
closely related analogues. By probing the structural basis of inhibition, we
discovered, using crystallographic methods, a new mode of high-affinity binding
in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens
of BABIM and two active site residues, His57 and Ser 195. Zn2+, at
subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct
Zn2+ coordination geometry implies a strong dependence of affinity on
substituents. This unique structural paradigm has enabled development of potent,
highly selective, Zn2+-dependent inhibitors of several therapeutically important
serine proteases, using a physiologically ubiquitous metal ion.
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Figure 1.
Figure 1 (2|F[o]| - |F[c]|),  [c]
map superimposed on the structure of trypsin-keto-BABIM-Zn2+, pH
8.2.
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Figure 2.
Figure 2 Superposition of trypsin-BABIM-Zn2+ onto
keto-BABIM-Zn2+. In the trypsin-BABIM-Zn2+ structure, carbons
are green, oxygens red, nitrogens blue and sulphurs yellow. In
the trypsin-keto-BABIM-Zn2+ structure, carbons are light blue,
oxygens orange, nitrogens rose, and sulphurs yellow.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(1998,
391,
608-612)
copyright 1998.
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