Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase.
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.
Davis
Mindy I
MI
Division of Biology 114-96 and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
Bennett
Melanie J
MJ
Thomas
Leonard M
LM
Bjorkman
Pamela J
PJ
D000595:Amino Acid Sequence; D000954:Antigens, Surface / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000737:chemistry*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013379:Substrate Specificity
D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D018076:DNA, Complementary; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II