A Remote Arene-Binding Site on Prostate Specific Membrane Antigen Revealed by Antibody-Recruiting Small Molecules

被引:134
作者
Zhang, Andrew X. [1 ]
Murelli, Ryan P. [1 ]
Barinka, Cyril [2 ]
Michel, Julien [1 ]
Cocleaza, Alexandra [1 ]
Jorgensen, William L. [1 ]
Lubkowski, Jacek [3 ]
Spiegel, David A. [1 ,4 ]
机构
[1] Yale Univ, Dept Chem, New Haven, CT 06510 USA
[2] Inst Biotechnol AS CR, VVI, Struct Biol Lab, Prague 14200 4, Czech Republic
[3] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA
[4] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
GLUTAMATE-CARBOXYPEPTIDASE-II; UREA-BASED INHIBITORS; AROMATIC STACKING INTERACTIONS; NATURAL ANTIBODIES; IMMUNE-RESPONSE; PSMA INHIBITOR; CANCER-THERAPY; DESIGN; CELLS; IMMUNOGLOBULINS;
D O I
10.1021/ja104591m
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页码:12711 / 12716
页数:6
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