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PDBsum entry 2c6c
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References listed in PDB file
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Key reference
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Title
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Structure of glutamate carboxypeptidase ii, A drug target in neuronal damage and prostate cancer.
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Authors
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J.R.Mesters,
C.Barinka,
W.Li,
T.Tsukamoto,
P.Majer,
B.S.Slusher,
J.Konvalinka,
R.Hilgenfeld.
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Ref.
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EMBO J, 2006,
25,
1375-1384.
[DOI no: ]
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PubMed id
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Abstract
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Membrane-bound glutamate carboxypeptidase II (GCPII) is a zinc metalloenzyme
that catalyzes the hydrolysis of the neurotransmitter
N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and L-glutamate
(which is itself a neurotransmitter). Potent and selective GCPII inhibitors have
been shown to decrease brain glutamate and provide neuroprotection in
preclinical models of stroke, amyotrophic lateral sclerosis, and neuropathic
pain. Here, we report crystal structures of the extracellular part of GCPII in
complex with both potent and weak inhibitors and with glutamate, the product of
the enzyme's hydrolysis reaction, at 2.0, 2.4, and 2.2 A resolution,
respectively. GCPII folds into three domains: protease-like, apical, and
C-terminal. All three participate in substrate binding, with two of them
directly involved in C-terminal glutamate recognition. One of the carbohydrate
moieties of the enzyme is essential for homodimer formation of GCPII. The
three-dimensional structures presented here reveal an induced-fit
substrate-binding mode of this key enzyme and provide essential information for
the design of GCPII inhibitors useful in the treatment of neuronal diseases and
prostate cancer.
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Figure 3.
Figure 3 Surface representation of the  20
Å deep funnel leading to the catalytic site. Blue,
side-chain nitrogens of Arg and Lys residues; red, side-chain
oxygens of Asp and Glu; green, side-chain carbons of Tyr and Phe
residues. Yellow, Zn^2+ ions; inhibitors shown as stick models.
(A) Complex with GPI-18431; (B) complex with phosphate. Note the
difference in the shape of the pocket because of withdrawal of
the 'glutarate sensor' (Y700) in the phosphate complex.
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Figure 4.
Figure 4 2F[o]–F[c] electron density maps (stereo) contoured
at 1.2  ,
for the GCPII complex with GPI-18431 (A), phosphate (B), and
L-glutamate (C). Zinc ions are shown in dark green, chloride in
yellow. Ligands are shown using green sticks and atom-color
spheres. Note the different conformation of the 'glutarate
sensor' (Lys699 and Tyr700) in (B), which is caused by the
absence of a glutarate moiety in the phosphate complex.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2006,
25,
1375-1384)
copyright 2006.
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