3IWW

Crystal structure of human glutamate carboxypeptidase II (GCPII) in a complex with DBIBzL, a urea-based inhibitor

Summary for 3IWW

• Entry DOI: 10.2210/pdb3iww/pdb
• Descriptor: Glutamate carboxypeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: prostate specific membrane antigen; metallopeptidase; folate hydrolase; glutamate carboxypeptidase ii; naaladase; urea-based inhibitor, carboxypeptidase, cell membrane, dipeptidase, glycoprotein, hydrolase, membrane, metal-binding, metalloprotease, multifunctional enzyme, protease, signal-anchor, transmembrane
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane ; Single-pass type II membrane protein . Isoform PSMA': Cytoplasm : Q04609
• Total number of polymer chains: 1
• Total formula weight: 83268.20

Authors

Barinka, C.,Lubkowski, J. (deposition date: 2009-09-03, release date: 2009-11-24, Last modification date: 2024-11-06)

Primary citation

Wang, H.,Byun, Y.,Barinka, C.,Pullambhatla, M.,Bhang, H.E.,Fox, J.J.,Lubkowski, J.,Mease, R.C.,Pomper, M.G.
Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies.
Bioorg.Med.Chem.Lett., 20:392-397, 2010

PubMed Abstract: We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1' site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with K(i) values below 20nM. Among them, compound 32d (K(i)=11nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1' pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d.

PubMed: 19897367
DOI: 10.1016/j.bmcl.2009.10.061

Experimental method

X-RAY DIFFRACTION (2.3 Å)