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  • The EMBO Journal (2006) 25, 1375 - 1384
  • doi:10.1038/sj.emboj.7600969

Published online: 9 February 2006

Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer

Jeroen R Mesters1,a, Cyril Barinka2,ab, Weixing Li3, Takashi Tsukamoto3, Pavel Majer3, Barbara S Slusher3, Jan Konvalinka2 and Rolf Hilgenfeld1

  1. Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany
  2. Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic, Prague, Czech Republic
  3. Guilford Pharmaceuticals Inc., Baltimore, MD, USA

Correspondence to:

Rolf Hilgenfeld, Institute of Biochemistry, Center for Structural and Cell Biology in Medicine (CSCM), University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. Tel.: +49 451 500 4060; Fax: +49 451 500 4068; E-mail: hilgenfeld@biochem.uni-luebeck.de

aThese authors contributed equally to this work

bPresent address: Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA

Received 1 September 2005; Accepted 23 December 2005

Membrane-bound glutamate carboxypeptidase II (GCPII) is a zinc metalloenzyme that catalyzes the hydrolysis of the neurotransmitter N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and L-glutamate (which is itself a neurotransmitter). Potent and selective GCPII inhibitors have been shown to decrease brain glutamate and provide neuroprotection in preclinical models of stroke, amyotrophic lateral sclerosis, and neuropathic pain. Here, we report crystal structures of the extracellular part of GCPII in complex with both potent and weak inhibitors and with glutamate, the product of the enzyme's hydrolysis reaction, at 2.0, 2.4, and 2.2 Å resolution, respectively. GCPII folds into three domains: protease-like, apical, and C-terminal. All three participate in substrate binding, with two of them directly involved in C-terminal glutamate recognition. One of the carbohydrate moieties of the enzyme is essential for homodimer formation of GCPII. The three-dimensional structures presented here reveal an induced-fit substrate-binding mode of this key enzyme and provide essential information for the design of GCPII inhibitors useful in the treatment of neuronal diseases and prostate cancer.

  • Keywords:

    • NAALADase,
    • neurodegenerative disease,
    • peptidase,
    • prostate cancer,
    • PSMA