title: Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II.
abstract: 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.
authors.affiliation: Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
authors.forename: Cyril
authors.initials: C
authors.lastname: Barinka
authors.forename: Miroslava
authors.initials: M
authors.lastname: Rovenská
authors.forename: Petra
authors.initials: P
authors.lastname: Mlcochová
authors.forename: Klára
authors.initials: K
authors.lastname: Hlouchová
authors.forename: Anna
authors.initials: A
authors.lastname: Plechanovová
authors.forename: Pavel
authors.initials: P
authors.lastname: Majer
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Jan
authors.initials: J
authors.lastname: Konvalinka
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubkowski
mesh_terms: D018360:Crystallography, X-Ray; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D011994:Recombinant Proteins; D043425:Glutamate Carboxypeptidase II