5D29
X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a hydroxamate inhibitor JHU241
Summary for 5D29
| Entry DOI | 10.2210/pdb5d29/pdb |
| Descriptor | Glutamate carboxypeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-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, ... (10 entities in total) |
| Functional Keywords | prostate-specific membrane antigen, naaladase, phosphoramidate, hydrolase |
| 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 | 81370.32 |
| Authors | Barinka, C.,Novakova, Z.,Pavlicek, J. (deposition date: 2015-08-05, release date: 2016-04-27, Last modification date: 2024-10-16) |
| Primary citation | Novakova, Z.,Wozniak, K.,Jancarik, A.,Rais, R.,Wu, Y.,Pavlicek, J.,Ferraris, D.,Havlinova, B.,Ptacek, J.,Vavra, J.,Hin, N.,Rojas, C.,Majer, P.,Slusher, B.S.,Tsukamoto, T.,Barinka, C. Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity. J.Med.Chem., 59:4539-4550, 2016 Cited by PubMed Abstract: Inhibition of glutamate carboxypeptidase II (GCPII) is effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. Here we report synthesis, structural characterization, and biological activity of new hydroxamic acid-based inhibitors with nanomolar affinity for human GCPII. Crystal structures of GCPII/hydroxamate complexes revealed an unprecedented binding mode in which the putative P1' glutarate occupies the spacious entrance funnel rather than the conserved glutamate-binding S1' pocket. This unique binding mode provides a mechanistic explanation for the structure-activity relationship data, most notably the lack of enantiospecificity and the tolerance for bulky/hydrophobic functions as substituents of a canonical glutarate moiety. The in vivo pharmacokinetics profile of one of the inhibitors will be presented along with analgesic efficacy data from the rat chronic constrictive injury model of neuropathic pain. PubMed: 27074627DOI: 10.1021/acs.jmedchem.5b01806 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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