4LQG

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

Summary for 4LQG

• Entry DOI: 10.2210/pdb4lqg/pdb
• Related PRD ID: PRD_001140
• Descriptor: 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)
• Functional Keywords: peptidase, hydrolase, metallopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 84164.10

Authors

Barinka, C.,Skultetyova, L. (deposition date: 2013-07-18, release date: 2014-12-31, Last modification date: 2020-07-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.77 Å)