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