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1: Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5981-6. Epub 2005 Apr 18.
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Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase.

Davis MI, Bennett MJ, Thomas LM, Bjorkman PJ.

Division of Biology 114-96 and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells and nonprostatic solid tumor neovasculature and is a target for anticancer imaging and therapeutic agents. PSMA acts as a glutamate carboxypeptidase (GCPII) on small molecule substrates, including folate, the anticancer drug methotrexate, and the neuropeptide N-acetyl-l-aspartyl-l-glutamate. Here we present the 3.5-A crystal structure of the PSMA ectodomain, which reveals a homodimer with structural similarity to transferrin receptor, a receptor for iron-loaded transferrin that lacks protease activity. Unlike transferrin receptor, the protease domain of PSMA contains a binuclear zinc site, catalytic residues, and a proposed substrate-binding arginine patch. Elucidation of the PSMA structure combined with docking studies and a proposed catalytic mechanism provides insight into the recognition of inhibitors and the natural substrate N-acetyl-l-aspartyl-l-glutamate. The PSMA structure will facilitate development of chemotherapeutics, cancer-imaging agents, and agents for treatment of neurological disorders.

Publication Types:
PMID: 15837926 [PubMed - indexed for MEDLINE]

PMCID: PMC556220