PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II (GCPII)-like. This group contains various PA domain-containing proteins similar to GCPII including, GCPIII (NAALADase2) and NAALADase L. These proteins belong to the peptidase M28 family. GCPII is also known N-acetylated-alpha-linked acidic dipeptidase (NAALDase1), folate hydrolase or prostate-specific membrane antigen (PSMA). GCPII is found in various human tissues including prostate, small intestine, and the central nervous system. In the brain, GCPII is known as NAALDase1, it functions as a NAALDase hydrolyzing the neuropeptide N-acetyl-L-aspartyl-L-glutamate (alpha-NAAG), to release free glutamate. In the small intestine, GCPII releases the terminal glutamate from poly-gamma-glutamated folates. GCPII (PSMA) is a useful cancer marker; its expression is markedly increased in prostate cancer and in tumor-associated neovasculature. GCPIII hydrolyzes alpha-NAAG with a lower efficiency than does GCPII; NAALADase L is not able to hydrolyze alpha-NAAG. The GCPII PA domain (referred to as the apical domain) participates in substrate binding and may act as a protein-protein interaction domain.
Structure:2C6C_A, human GCPII, bound with an inhibitor Gpi-18431 (S)-2-(4- Iodobenzylphosphonomethyl)-Pentanedioic Acid, contacts with inhibitor at 3.5A
Structure:2C6G_A, human GCPII, bound with glutamate (the product of the reaction), contacts with glutamate at 3.5 A
Comment:The 2C6C_A and 2C6G_A structures show the PA (apical) domain interacting, with the glutarate portion of the GPI-18431 inhibitor, and with the glutamate product, respectively. The interacting PA residues form part of the GPCII S1' substrate-binding pocket. The inhibitor GPI-18431 occupies the S1 and S1' pockets; Glutamate occupies only the S1' pocket.
Jiyao W et al.(2023). "The conserved domain database in 2023.",