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PDBsum entry 2jbk
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References listed in PDB file
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Key reference
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Title
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Human glutamate carboxypeptidase ii inhibition: structures of gcpii in complex with two potent inhibitors, Quisqualate and 2-Pmpa.
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Authors
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J.R.Mesters,
K.Henning,
R.Hilgenfeld.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2007,
63,
508-513.
[DOI no: ]
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PubMed id
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Abstract
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Human glutamate carboxypeptidase II (GCPII) occurs in the central nervous system
as well as in human prostate (where it is called prostate-specific membrane
antigen; PSMA). Inhibitors of the enzyme have been shown to provide
neuroprotection, but may also be useful for the detection, imaging and treatment
of prostate cancer. Crystal structures were determined of the extracellular part
of GCPII (amino-acid residues 44-750) in complex with two potent inhibitors,
quisqualate and 2-PMPA (the strongest GCPII inhibitor to date), at resolutions
of 3.0 and 2.2 A, respectively. In addition, models were constructed for binding
of the inhibitors willardiine, homoibotenate, L-2-amino-4-phosphonobutanoic acid
and L-serine-O-sulfate to the S1' site of the enzyme. The common denominator for
high-affinity binding to the S1' site is the formation of two strong salt
bridges.
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Figure 1.
Figure 1 (a) Binding mode of glutamate to the S1' pocket of
GCPII. (b)-(g) Chemical formulae of 2-PMPA (b), L-AP4 (c), L-SOS
(d), quisqualate (e), HIBO (f) and willardiine (g).
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The above figure is
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2007,
63,
508-513)
copyright 2007.
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Secondary reference #1
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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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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
reproduced from the cited reference
which is an Open Access publication published by Macmillan Publishers Ltd
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