Title : Structural insight into the evolutionary and pharmacologic homology of
glutamate carboxypeptidases II and III
Abstract :
- Glutamate carboxypeptidase III ( GCPIII ) is a metalloenzyme that belongs to the transferrin receptor/ glutamate carboxypeptidase II ( GCPII ; EC 3.4.17.21) superfamily
- GCPIII has been studied mainly because of its evolutionary relationship to GCPII , an enzyme involved in a variety of neuropathologies and malignancies, such as glutamatergic neurotoxicity and prostate cancer
- Given the potential functional and pharmacological overlap between GCPIII and GCPII , studies addressing the structural and physiological properties of GCPIII are crucial for obtaining a deeper understanding of the GCPII / GCPIII system
- In the present study, we report high-resolution crystal structures of the human GCPIII ectodomain in a 'pseudo-unliganded' state and in a complex with: (a) L-glutamate (a product of hydrolysis); (b) a phosphapeptide transition state mimetic, namely (2S,3'S)-{[(3'-amino-3'-carboxy-propyl)-hydroxyphosphinoyl]methyl}-pentanedioic acid; and (c) quisqualic acid, a glutamate biostere
- Our data reveal the overall fold and quaternary arrangement of the GCPIII molecule, define the architecture of the GCPIII substrate-binding cavity, and offer an experimental evidence for the presence of Zn(2+) ions in the bimetallic active site
- Furthermore, the structures allow us to detail interactions between the enzyme and its ligands and to characterize the functional flexibility of GCPIII , which is essential for substrate recognition
- A comparison of these GCPIII structures with the equivalent GCPII complexes reveals differences in the organization of specificity pockets, in surface charge distribution, and in the occupancy of the co-catalytic zinc sites
- The data presented here provide information that should prove to be essential for the structurally-aided design of GCPIII-specific inhibitors and might comprise guidelines for future comparative GCPII / GCPIII studies