2XEF

Human glutamate carboxypeptidase II in complex with Antibody- Recruiting Molecule ARM-P8

2XEF の概要

• エントリーDOI: 10.2210/pdb2xef/pdb
• 関連するPDBエントリー: 1Z8L 2C6C 2C6G 2C6P 2CIJ 2JBJ 2JBK 2XEG 2XEI 2XEJ
• 分子名称: GLUTAMATE CARBOXYPEPTIDASE 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-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)
• 機能のキーワード: metallopeptidase, hydrolase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cell membrane; Single-pass type II membrane protein. Isoform PSMA': Cytoplasm: Q04609
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 83686.77

構造登録者

Zhang, A.X.,Murelli, R.P.,Barinka, C.,Michel, J.,Cocleaza, A.,Jorgensen, W.L.,Lubkowski, J.,Spiegel, D.A. (登録日: 2010-05-14, 公開日: 2010-09-08, 最終更新日: 2024-11-13)

主引用文献

Zhang, A.X.,Murelli, R.P.,Barinka, C.,Michel, J.,Cocleaza, A.,Jorgensen, W.L.,Lubkowski, J.,Spiegel, D.A.
A Remote Arene-Binding Site on Prostate Specific Membrane Antigen Revealed by Antibody-Recruiting Small Molecules.
J.Am.Chem.Soc., 132:12711-, 2010

PubMed Abstract: Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. Our laboratory has recently disclosed a class of small molecules, called ARM-Ps (antibody-recruiting molecule targeting prostate cancer) that are capable of enhancing antibody-mediated immune recognition of prostate cancer cells. Interestingly, during the course of these studies, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth biochemical, crystallographic, and computational investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs. Although this site is composed of only a few amino acid residues, it drastically enhances small molecule binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment; more broadly, the presence of similar arene-binding sites throughout the proteome could prove widely enabling in the optimization of small molecule-protein interactions.

PubMed: 20726553
DOI: 10.1021/JA104591M

実験手法

X-RAY DIFFRACTION (1.59 Å)