4NGN

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

4NGN の概要

• エントリーDOI: 10.2210/pdb4ngn/pdb
• 関連するPDBエントリー: 4NGM 4NGP 4NGQ 4NGR 4NGS 4NGT
• 分子名称: 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)
• 機能のキーワード: hydrolase, glutamate carboxypeptidase ii, psma, naaladase, urea-based inhibitor, caboxypeptidase, glycoprotein, metallopeptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 87577.07

構造登録者

Tykvart, J.,Pachl, P. (登録日: 2013-11-02, 公開日: 2014-06-18, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.64 Å)