4LQG

X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a phosphoramidate inhibitor CTT1056

4LQG の概要

• エントリーDOI: 10.2210/pdb4lqg/pdb
• 関連するBIRD辞書のPRD_ID: PRD_001140
• 分子名称: Glutamate carboxypeptidase 2, N-(4-fluorobenzoyl)-L-gamma-glutamyl-5-{[(S)-{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]oxy}-L-norvaline, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: peptidase, hydrolase, metallopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 84164.10

構造登録者

Barinka, C.,Skultetyova, L. (登録日: 2013-07-18, 公開日: 2014-12-31, 最終更新日: 2024-11-27)

主引用文献

Dannoon, S.,Ganguly, T.,Cahaya, H.,Geruntho, J.J.,Galliher, M.S.,Beyer, S.K.,Choy, C.J.,Hopkins, M.R.,Regan, M.,Blecha, J.E.,Skultetyova, L.,Drake, C.R.,Jivan, S.,Barinka, C.,Jones, E.F.,Berkman, C.E.,VanBrocklin, H.F.
Structure-Activity Relationship of (18)F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer.
J.Med.Chem., 59:5684-5694, 2016

PubMed Abstract: A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.

PubMed: 27228467
DOI: 10.1021/acs.jmedchem.5b01850

実験手法

X-RAY DIFFRACTION (1.77 Å)