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PDBsum entry 2or4
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References listed in PDB file
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Key reference
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Title
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Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase ii.
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Authors
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C.Barinka,
M.Rovenská,
P.Mlcochová,
K.Hlouchová,
A.Plechanovová,
P.Majer,
T.Tsukamoto,
B.S.Slusher,
J.Konvalinka,
J.Lubkowski.
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Ref.
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J Med Chem, 2007,
50,
3267-3273.
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PubMed id
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Abstract
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Inhibition of glutamate carboxypeptidase II (GCPII) has been shown to be
neuroprotective in multiple preclinical models in which dysregulated
glutamatergic transmission is implicated. Herein, we report crystal structures
of the human GCPII complexed with three glutamate mimetics/derivatives,
2-(phosphonomethyl)pentanedioic acid (2-PMPA), quisqualic acid (QA), and
L-serine O-sulfate (L-SOS), at 1.72, 1.62, and 2.10 A resolution, respectively.
Despite the structural differences between the distal parts of the inhibitors,
all three compounds share similar binding modes in the pharmacophore (i.e., S1')
pocket of GCPII, where they are stabilized by a combination of polar and van der
Waals interactions. The structural diversity of the distal parts of the
inhibitors leads to rearrangements of the S1' site that are necessary for
efficient interactions between the enzyme and an inhibitor. The set of
structures presented here, in conjunction with the available biochemical data,
illustrates a flexibility of the GCPII pharmacophore pocket and highlights the
structural features required for potent GCPII inhibition. These findings could
facilitate the rational structure-based drug design of new GCPII inhibitors in
the future.
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