期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 132, 期 36, 页码 12711-12716出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja104591m
关键词
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资金
- National Institutes of Health [DP22OD002913, GM32136]
- EMBO [1978]
- IBT [CEZ:AV0Z50520701]
- U.S. Department of Energy [W-31-109-Eng38]
- National Cancer Institute, Center for Cancer Research
- National Science Foundation [TG-CHE090106]
- European Community [FP7-PEOPLE-2008-16704-1-IOF, 234796-PPIdesign]
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.
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