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

Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5981-6. doi: 10.1073/pnas.0502101102. Epub 2005 Apr 18.

Abstract

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antigens, Surface / chemistry*
  • Antigens, Surface / metabolism*
  • Binding Sites
  • Biomarkers, Tumor / chemistry*
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • Glutamate Carboxypeptidase II / chemistry*
  • Glutamate Carboxypeptidase II / metabolism*
  • Humans
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Protein Structure, Secondary
  • Substrate Specificity

Substances

  • Antigens, Surface
  • Biomarkers, Tumor
  • DNA, Complementary
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II

Associated data

  • PDB/1Z8L