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PDBsum entry 1bjv
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Serine protease
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PDB id
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1bjv
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References listed in PDB file
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Key reference
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Title
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Oxyanion-Mediated inhibition of serine proteases.
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Authors
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S.R.Presnell,
G.S.Patil,
C.Mura,
K.M.Jude,
J.M.Conley,
J.A.Bertrand,
C.M.Kam,
J.C.Powers,
L.D.Williams.
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Ref.
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Biochemistry, 1998,
37,
17068-17081.
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PubMed id
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Abstract
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Novel aryl derivatives of benzamidine were synthesized and tested for their
inhibitory potency against bovine trypsin, rat skin tryptase, human recombinant
granzyme A, human thrombin, and human plasma kallikrein. All compounds show
competitive inhibition against these proteases with Ki values in the micromolar
range. X-ray structures were determined to 1.8 A resolution for trypsin
complexed with two of the para-substituted benzamidine derivatives,
1-(4-amidinophenyl)-3-(4-chlorophenyl)urea (ACPU) and
1-(4-amidinophenyl)-3-(4-phenoxyphenyl)urea (APPU). Although the inhibitors do
not engage in direct and specific interactions outside the S1 pocket, they do
form intimate indirect contacts with the active site of trypsin. The inhibitors
are linked to the enzyme by a sulfate ion that forms an intricate network of
three-centered hydrogen bonds. Comparison of these structures with other serine
protease structures with noncovalently bound oxyanions reveals a pair of highly
conserved oxyanion-binding sites in the active site. The positions of
noncovalently bound oxyanions, such as the oxygen atoms of sulfate, are distinct
from the positions of covalent oxyanions of tetrahedral intermediates.
Noncovalent oxyanion positions are outside the "oxyanion hole." Kinetics data
suggest that protonation stabilizes the ternary inhibitor/oxyanion/protease
complex. In sum, both cations and anions can mediate Ki. Cation mediation of
potency of competitive inhibitors of serine proteases was previously reported by
Stroud and co-workers [Katz, B. A., Clark, J. M., Finer-Moore, J. S., Jenkins,
T. E., Johnson, C. R., Ross, M. J., Luong, C., Moore, W. R., and Stroud, R. M.
(1998) Nature 391, 608-612].
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Secondary reference #1
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Title
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The refined crystal structure of bovine beta-Trypsin at 1.8 a resolution. Ii. Crystallographic refinement, Calcium binding site, Benzamidine binding site and active site at ph 7.0.
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Authors
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W.Bode,
P.Schwager.
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Ref.
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J Mol Biol, 1975,
98,
693-717.
[DOI no: ]
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PubMed id
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Figure 4.
FiG. 4. Stereo pair of the calcium-bindng loop including the calcium ion and internal water
molecules.
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Figure 7.
Fro. 7. Stereo pair of the region aroun the salt bridge between the benzamidine and Asp189
in benzamidine-inhibited trpsin (a) and side chain of LyslS(I) an Asp189 in he trysin-
inhibitor complex (b), both in complex orientation.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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