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

谷氨酸羧肽酶Ⅱ 化学 小分子 前列腺癌 抗体 抗原 结合位点 分子 生物化学 癌症 计算生物学 生物物理学 免疫学 生物 遗传学 有机化学
作者
Andrew X. Zhang,Ryan P. Murelli,Cyril Bařinka,Julien Michel,A. Cocleaza,William L. Jorgensen,J. Łubkowski,David A. Spiegel
出处
期刊:Journal of the American Chemical Society [American Chemical Society]
卷期号:132 (36): 12711-12716 被引量:131
标识
DOI:10.1021/ja104591m
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.
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