5D29

X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a hydroxamate inhibitor JHU241

5D29 の概要

• エントリーDOI: 10.2210/pdb5d29/pdb
• 分子名称: 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)
• 機能のキーワード: prostate-specific membrane antigen, naaladase, phosphoramidate, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Single-pass type II membrane protein . Isoform PSMA': Cytoplasm : Q04609
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 81370.32

構造登録者

Barinka, C.,Novakova, Z.,Pavlicek, J. (登録日: 2015-08-05, 公開日: 2016-04-27, 最終更新日: 2024-10-16)

主引用文献

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

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: 27074627
DOI: 10.1021/acs.jmedchem.5b01806

実験手法

X-RAY DIFFRACTION (1.8 Å)