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Interactions between Human Glutamate Carboxypeptidase II and Urea-Based Inhibitors: Structural Characterization

  1. Author:
    Barinka, C.
    Byun, Y.
    Dusich, C. L.
    Banerjee, S. R.
    Chen, Y.
    Castanares, M.
    Kozikowski, A. P.
    Mease, R. C.
    Pomper, M. G.
    Lubkowski, J.

  2. Author Address

    Barinka, Cyril, Lubkowski, Jacek] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Castanares, Mark, Pomper, Martin G.] Johns Hopkins Med Inst, Dept Pharmacol & Mol Sci, Baltimore, MD 21231 USA. [Kozikowski, Alan P.] Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. [Byun, Youngjoo, Dusich, Crystal L.; Banerjee, Sangeeta R.; Chen, Ying, Mease, Ronnie C.; Pomper, Martin G.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21231 USA.
    1. Year: 2008
  2. Journal: Journal of Medicinal Chemistry
    1. 51
    2. 24
    3. Pages: 7737-7743
  4. Type of Article: Article
  1. Abstract:

    Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and call 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 in 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 S I 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 call be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.

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External Sources

  1. PMID: 19053759

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