Observing Protein Allostery Dynamics by Single-Particle Imaging

Type of Award: Catalyst
Date Awarded: March 2018
Award End Date: February 2020
Amount Awarded: $ 250,000.00
PI(s): Xiaojing Yang, UIC; Minglei Zhao, UChicago;

Abstract: Allosteric regulation of protein function is central to many important biological processes in cell signaling and disease biology. Because allosteric action involves long-range communication in protein structures, watching the structural dynamics of these macromolecules at work holds the key for mechanistic understanding of their function and thereby for developing new strategies to address human diseases caused by impaired regulation. However, currently, there is no biophysical method for direct observation of large-scale protein dynamics at atomic or near-atomic resolution. Here we propose to develop a novel methodology for direct imaging and quantitative analysis of functionally relevant structural dynamics in macromolecular complexes by transforming cryo-electron microscopy (cryo-EM) from an imaging technique to a dynamic approach. This challenging approach promises to provide mechanistic insights that cannot be obtained by other means. It will reveal precisely how protein function is controlled and how impaired allosteric regulation of protein function might be targeted with drugs.