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PDBsum entry 1h4w
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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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Crystal structure reveals basis for the inhibitor resistance of human brain trypsin.
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Authors
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G.Katona,
G.I.Berglund,
J.Hajdu,
L.Gráf,
L.Szilágyi.
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Ref.
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J Mol Biol, 2002,
315,
1209-1218.
[DOI no: ]
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PubMed id
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Abstract
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Severe neurodegradative brain diseases, like Alzheimer, are tightly linked with
proteolytic activity in the human brain. Proteinases expressed in the brain,
such as human trypsin IV, are likely to be involved in the pathomechanism of
these diseases. The observation of amyloid formed in the brain of transgenic
mice expressing human trypsin IV supports this hypothesis. Human trypsin IV is
also resistant towards all studied naturally occurring polypeptide inhibitors.
It has been postulated that the substitution of Gly193 to arginine is
responsible for this inhibitor resistance. Here we report the X-ray structure of
human trypsin IV in complex with the inhibitor benzamidine at 1.7 A resolution.
The overall fold of human trypsin IV is similar to human trypsin I, with a
root-mean square deviation of only 0.5 A for all C(alpha) positions. The crystal
structure reveals the orientation of the side-chain of Arg193, which occupies an
extended conformation and fills the S2' subsite. An analysis of surface
electrostatic potentials shows an unusually strong clustering of positive
charges around the primary specificity pocket, to which the side-chain of Arg193
also contributes. These unique features of the crystal structure provide a
structural basis for the enhanced inhibitor resistance, and enhanced substrate
restriction, of human trypsin IV.
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Figure 4.
Figure 4. Electrostatic potential mapped onto the molecular
surface of (a) human trypsin IV, (b) human trypsin I, (c) rat
anionic trypsin and (d) bovine cationic trypsin. The contouring
level of electrostatic potential is -18 kT/e (red) and 18 kT/e
(blue). The orientation of the molecules is the same as in
Figure 1(a).
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Figure 5.
Figure 5. (a) View of the N-terminal loop of human trypsin
IV. The SigmaA weighted 2mF[o] - DF[c] electron density map is
contoured at 1s level. (b) Structural comparison of the
N-terminal loops in human trypsin IV (black), human trypsin I
(green), rat trypsin (cyan), bovine trypsin (magenta). Two
alternative conformations are shown for Leu27.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2002,
315,
1209-1218)
copyright 2002.
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