6S1X

X-ray structure of human glutamate carboxypeptidase II (GCPII)-E424M inactive mutant, in complex with a inhibitor KB1160

Summary for 6S1X

• Entry DOI: 10.2210/pdb6s1x/pdb
• Descriptor: Glutamate carboxypeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: glutamate carboxypeptidase ii (gcpii); naaladase; prostate-specific membrane antigen; urea-based inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 83425.31

Authors

Barinka, C.,Kutil, Z. (deposition date: 2019-06-19, release date: 2020-05-13, Last modification date: 2024-10-23)

Primary citation

Kim, K.,Kwon, H.,Barinka, C.,Motlova, L.,Nam, S.,Choi, D.,Ha, H.,Nam, H.,Son, S.H.,Minn, I.,Pomper, M.G.,Yang, X.,Kutil, Z.,Byun, Y.
Novel beta- and gamma-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen.
J.Med.Chem., 63:3261-3273, 2020

PubMed Abstract: Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine the effect of β- and γ-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the β- and γ-amino acid analogues with ()- or ()-configuration with keeping α-(l)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound , a β-amino acid analogue with ()-configuration, exhibited the most potent PSMA inhibitory activity with an IC value of 3.97 nM. The X-ray crystal structure of PSMA in complex with provided a mechanistic basis for the stereochemical preference of PSMA, which can guide the development of future PSMA inhibitors.

PubMed: 32097010
DOI: 10.1021/acs.jmedchem.9b02022

Experimental method

X-RAY DIFFRACTION (1.76 Å)