Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: Structural characterization

Cyril Barinka, Youngjoo Byun, Crystal L. Dusich, Sangeeta R. Banerjee, Ying Chen, Mark Castanares, Alan P. Kozikowski, Ronnie C. Mease, Martin G. Pomper, Jacek Lubkowski

Research output: Contribution to journalArticle

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 Zn12+ 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.

Original languageEnglish (US)
Pages (from-to)7737-7743
Number of pages7
JournalJournal of medicinal chemistry
Volume51
Issue number24
DOIs
StatePublished - Dec 25 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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