3D7H

A high resolution crystal structure of human glutamate carboxypeptidase II (GCPII) in a complex with DCIBzL, a urea-based inhibitor

Summary for 3D7H

• Entry DOI: 10.2210/pdb3d7h/pdb
• Related: 3D7D 3D7F 3D7G
• Descriptor: Glutamate carboxypeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: prostate specific membrane antigen (psma); metallopeptidase; folate hydrolase; glutamate carboxypeptidase ii; naaladase, dcibzl, urea-based inhibitor, carboxypeptidase, dipeptidase, glycoprotein, hydrolase, membrane, metal-binding, metalloprotease, multifunctional enzyme, protease, signal-anchor, transmembrane
• Biological source: Homo sapiens
• Cellular location: Cell membrane; Single-pass type II membrane protein. Isoform PSMA': Cytoplasm: Q04609
• Total number of polymer chains: 1
• Total formula weight: 83462.34

Authors

Lubkowski, J.,Barinka, C. (deposition date: 2008-05-21, release date: 2008-12-30, Last modification date: 2024-10-16)

Primary citation

Barinka, C.,Byun, Y.,Dusich, C.L.,Banerjee, S.R.,Chen, Y.,Castanares, M.,Kozikowski, A.P.,Mease, R.C.,Pomper, M.G.,Lubkowski, J.
Interactions between Human Glutamate Carboxypeptidase II and Urea-Based Inhibitors: Structural Characterization
J.Med.Chem., 51:7737-7743, 2008

PubMed Abstract: Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and can serve as imaging agents for prostate cancer. To enhance further development of such compounds, we determined X-ray structures of four complexes between human GCPII and urea-based inhibitors at high resolution. All ligands demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme. The ureido linkage between P1 and P1' inhibitor sites interacts with the active-site Zn(1)(2+) ion and the side chains of Tyr552 and His553. Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.

PubMed: 19053759
DOI: 10.1021/jm800765e

Experimental method

X-RAY DIFFRACTION (1.55 Å)