4NGM
Crystal Structure of Glutamate Carboxypeptidase II in a complex with urea-based inhibitor
Summary for 4NGM
| Entry DOI | 10.2210/pdb4ngm/pdb |
| Related | 4NGN 4NGP 4NGQ 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, glutamate carboxypeptidase ii, psma, naaladase, urea-based inhibitor, caboxypeptidase, glycoprotein, metallopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 87191.31 |
| Authors | Tykvart, J.,Pachl, P. (deposition date: 2013-11-02, release date: 2014-06-18, Last modification date: 2024-10-30) |
| 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 Cited by 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: 24954515DOI: 10.1016/j.bmc.2014.05.061 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.84 Å) |
Structure validation
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