A General Supramolecular Approach to Regulate Protein Functions by Cucurbit[7]uril and Unnatural Amino Acid Recognition

• Published in: Angewandte Chemie International Edition Vol. 60; no. 20; pp. 11196 - 11200
• Main Authors: Cao, Wenbing, Qin, Xuewen, Wang, Yong, Dai, Zhen, Dai, Xianyin, Wang, Haoyu, Xuan, Weimin, Zhang, Yingming, Liu, Yu, Liu, Tao
• Format: Journal Article
• Language: English
• Published: Germany 10.05.2021
• Subjects: cytokines; enzymes; protein function; supramolecular chemistry; unnatural amino acids; enzymes; cytokines; protein function; unnatural amino acids; supramolecular chemistry
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202100916

Regulation of specific protein function is of great importance for both research and therapeutic development. Many small or large molecules have been developed to control specific protein function, but there is a lack of a universal approach to regulate the function of any given protein. We report a general host–guest molecular recognition approach involving modification of the protein functional surfaces with genetically encoded unnatural amino acids bearing guest side chains that can be specifically recognized by cucurbit[7]uril. Using two enzymes and a cytokine as models, we showed that the activity of proteins bearing unnatural amino acid could be turned off by host molecule binding, which blocked its functional binding surface. Protein activity can be switched back by treatment with a competitive guest molecule. Our approach provides a general tool for reversibly regulating protein function through molecular recognition and can be expected to be valuable for studying protein functions. A universal supramolecular host–guest recognition strategy was developed for reversible regulation of protein function at the single residue level. A guest molecule that can be specifically recognized by cucurbit[7]uril was genetically encoded into proteins. Reversible regulation of enzyme function and cell activity was achieved when this strategy was applied to two enzymes and a cytokine.