4NGQ

Crystal Structure of Glutamate Carboxypeptidase II in a complex with urea-based inhibitor

Summary for 4NGQ

• Entry DOI: 10.2210/pdb4ngq/pdb
• Related: 3D7H 4NGM 4NGN 4NGP 4NGR 4NGS 4NGT
• Descriptor: Glutamate carboxypeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: hydrolase, metallopeptidase, glycoprotein, urea-based inhibitor, trasmembrane, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 87786.11

Authors

Tykvart, J.,Pachl, P. (deposition date: 2013-11-02, release date: 2014-06-18, Last modification date: 2024-10-16)

Primary citation

Tykvart, J.,Schimer, J.,Barinkova, J.,Pachl, P.,Postova-Slavetinska, L.,Majer, P.,Konvalinka, J.,Sacha, P.
Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery.
Bioorg.Med.Chem., 22:4099-4108, 2014

PubMed Abstract: Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate cancer marker and is considered a promising target for specific anticancer drug delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and drug delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII.

PubMed: 24954515
DOI: 10.1016/j.bmc.2014.05.061

Experimental method

X-RAY DIFFRACTION (2.08 Å)