Understanding Protein Allostery
Allosteric enzymes are key players in the signaling pathways that enable cells to respond to changes inside and outside their cell walls. These shape-shifting proteins catalyze biochemical reactions in a chain of cascading molecular events that carry signals forward. Through a mechanism called allostery, chemical modulators can alter enzymatic behavior by binding to an enzyme at a site distinct from the active site of catalysis. Correlated motions in the enzyme’s molecular configuration then transmit the modulator’s presence to the active site, where catalytic activity is either stimulated or inhibited.
With this CAREER award, Nozomi Ando, Chemistry and Chemical Biology, is elucidating the biomolecular dynamics underlying protein allostery by relating correlated motions in enzymes to protein sequence. The research focuses on ribonucleotide reductase enzymes, which perform a key reaction for all DNA-based life.
The project takes the unprecedented approach of interfacing advanced x-ray scattering methods with single-particle cryo-electron microscopy, computational bioinformatics, and other complementary techniques. Researchers will employ statistical and phylogenetic inference methods to determine evolutionary correlations of protein sequences and to understand how allosteric mechanisms emerge and evolve. They will use cryo-electron microscopy and x-ray scattering to study the relationships between correlated motions and protein sequence.
Allostery allows for tight regulation of enzymatic activity to conserve cellular resources. This research will contribute to fundamental insights into biomolecular dynamics essential to life, with applications ranging from drug development to biochemical engineering.