Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase

摘要

Division of Biology 114-96, California Institute of Technology, Pasadena, CA 91125 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 metho-trexate, and the neuropeptide N-acetyl-L-aspartyl-L-glutamate. Here we present the 3.5-A crystal structure of the PSMA ectodo-main, 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.