Title : Interactions between human
glutamate carboxypeptidase II and urea-based inhibitors: structural characterization
Abstract :
- Urea-based, low molecular weight ligands of glutamate carboxypeptidase II ( GCPII ) have demonstrated efficacy in various models of neurological disorders and can serve as imaging agents for prostate cancer
- To enhance further development of such compounds, we determined X-ray structures of four complexes between human GCPII and urea-based inhibitors at high resolution
- All ligands demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme
- The ureido linkage between P1 and P1' inhibitor sites interacts with the active-site Zn(1)(2+) ion and the side chains of Tyr552 and His553
- Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519
- Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity