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4lqg

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

Structural highlights

4lqg is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.77Å
Ligands:	, , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FOLH1_HUMAN Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoform PSM-4 and isoform PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression. Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.

Publication Abstract from PubMed

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 [18F]4, [18F]5, and [18F]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 [18F]5 and [18F]6 as favorable candidates for future prostate cancer imaging clinical trials.

Structure-Activity Relationship of F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer.,Dannoon S, Ganguly T, Cahaya H, Geruntho JJ, Galliher MS, Beyer SK, Choy CJ, Hopkins MR, Regan M, Blecha JE, Skultetyova L, Drake CR, Jivan S, Barinka C, Jones EF, Berkman CE, VanBrocklin HF J Med Chem. 2016 Jun 13. PMID:27228467^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dannoon S, Ganguly T, Cahaya H, Geruntho JJ, Galliher MS, Beyer SK, Choy CJ, Hopkins MR, Regan M, Blecha JE, Skultetyova L, Drake CR, Jivan S, Barinka C, Jones EF, Berkman CE, VanBrocklin HF. Structure-Activity Relationship of F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer. J Med Chem. 2016 Jun 13. PMID:27228467 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01850