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PDBsum entry 1orv
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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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The crystal structure of dipeptidyl peptidase IV (cd26) reveals its functional regulation and enzymatic mechanism.
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Authors
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M.Engel,
T.Hoffmann,
L.Wagner,
M.Wermann,
U.Heiser,
R.Kiefersauer,
R.Huber,
W.Bode,
H.U.Demuth,
H.Brandstetter.
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Ref.
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Proc Natl Acad Sci U S A, 2003,
100,
5063-5068.
[DOI no: ]
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PubMed id
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Abstract
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The membrane-bound glycoprotein dipeptidyl peptidase IV (DP IV, CD26) is a
unique multifunctional protein, acting as receptor, binding and proteolytic
molecule. We have determined the sequence and 1.8 A crystal structure of native
DP IV prepared from porcine kidney. The crystal structure reveals a 2-2-2
symmetric tetrameric assembly which depends on the natively glycosylated
beta-propeller blade IV. The crystal structure indicates that tetramerization of
DP IV is a key mechanism to regulate its interaction with other components. Each
subunit comprises two structural domains, the N-terminal eight-bladed
beta-propeller with open Velcro topology and the C-terminal alpha/beta-hydrolase
domain. Analogy with the structurally related POP and tricorn protease suggests
that substrates access the buried active site through the beta-propeller tunnel
while products leave the active site through a separate side exit. A dipeptide
mimicking inhibitor complexed to the active site discloses key determinants for
substrate recognition, including a Glu-Glu motif that distinguishes DP IV as an
aminopeptidase and an oxyanion trap that binds and activates the P(2)-carbonyl
oxygen necessary for efficient postproline cleavage. We discuss active and
nonactive site-directed inhibition strategies of this pharmaceutical target
protein.
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Figure 2.
Fig. 2. Soluble DP IV forms a 222 symmetric assembly as a
dimer of dimers. The view is along one two-fold axis. Potential
glycosylation sites are indicated as gray spheres, and red
spheres are the sites modified in our crystal structure. The
transmembrane helices and their orientation to the membrane were
modeled to illustrate how tetramerization of DP IV can mediate
cell-cell contacts. The figures were prepared by using the
programs MAIN (25), MOLSCRIPT (55), and RASTER3D (56).
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Figure 5.
Fig. 5. Substrate recognition by DP IV. (a) The
peptidomimetic inhibitor p-Iodo-Phe-Pyr-CN is covalently bound
to active site Ser-630. The accessible surface is indicated and
cut open (dark green) for better visibility. (b) Schematic
representation of the active site access in tricorn and DP IV.
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