(4ar) Design of Novel Artificial Allosteric Proteins and Their Applications

Li, J., the Ohio State University
Wood, D. W., The Ohio State University

Allosteric regulation of protein function is one of essential pathways for cellular processes. The basic feature for natural allosteric proteins is that ligand binding will induce a significant conformational alteration and subsequently influence their activity. Inspired by this mechanism, artificial allosteric proteins might be developed from various receptor proteins as artificial molecular switches. While nuclear receptors, with their inherent molecular switch behavior, are suitable for directly coupling ligand binding with a reporter protein or enzyme, other natural receptors may require a synthetic allosteric domain. With the advancement of directed-evolution technology, robust artificial binding proteins originating from engineered scaffolds with high stability and affinity can be easily generated. These artificial affinity proteins might serve as an abundant source for artificial allosteric proteins, either through coupling with natural allosteric domains or synthetic switches. These artificial allosteric proteins might then be used to control metabolic pathways for target optimization, or be used to interfere with the transcription of target genes for therapeutic applications. They may even be able to directly act as controllable therapeutics for a series of severe diseases such as cancer and cardiovascular disorders. In this context, binding of the allosteric protein to the target receptor or target protein will activate or release a functional domain. On the other hand, the linkage of affinity proteins with reporter enzyme can be used to develop highly sensitive biosensors for drug discovery. In this poster, the basic strategy for the design of artificial allosteric proteins and the potential applications of these proteins will be introduced and discussed.