“We’ve found evidence that atomic motions in proteins play a major role in impacting their function,” said David Giedroc, Lilly Chemistry Alumni Professor at the Indiana University Bloomington College of Arts and Sciences’ Department of Chemistry. These atomic motions dictate protein structure and function, and since proteins serve as important drug targets, this research finding especially resonates with scientists focusing on drug discovery, design and development. Since this is what I’m studying too, these findings speak to me! They are INTRIGUING!
“Atomic motions can be optimized for function more easily than a physical structure”, pointed out Daiana A. Capdevila, a postdoctoral researcher in Giedroc’s lab, who is first author on the study. Giedroc and his team showed that atomic-level motional disorder (or entropy) influences gene transcription to significantly impact protein functions. Altered protein function may aid the bacteria to “evolve new ways” to rapidly and stealthily evade medical treatment. Since “these (atomic) motions can be ‘tuned’ evolutionarily”, according to Capdevila, we have been witnessing the evolution of drug-resistant bacteria.
Giedroc and colleagues specifically studied CzrA, a bacterial protein responsible for regulating zinc levels within the microorganism. This is a key ability that helps them resist assault by the human immune system.
“CzrA controls a biological mechanism in bacteria called the ‘zinc pump,’ which pushes extra zinc out of bacterial cells in response to the immune system’s attempts to poison them with the metal,” Giedroc explained. The group discovered unpredicted areas on the CzrA molecule that played a role in zinc regulation. “There’s no way anyone could have predicted these areas played a role in zinc regulation by simply looking at the protein structure,” said Giedroc. “Once you know where these ‘hot spots’ are located, however, it’s theoretically possible to design a small molecule or drug…to essentially shut off the protein.”
This, in effect, is the concept underlying a novel class of drugs termed “allosteric drugs” which are so called as they target/bind to areas on a protein- called allosteric sites- that mediate the primary function of the protein, for example zinc binding, without binding to the site on the protein that regulates its primary function.
Giedroc observed that this is all about adopting a holistic approach towards studying protein function where it’s imperative to look at the ‘functions of proteins in the context of a network- not simply targeting a single strategic point…’. “And this particular study shows the most effective way to gain this deeper knowledge requires going beyond the molecular level in proteins to understand how atomic motion plays a role in function — after which you can start applying that knowledge to designing more effective drug-based therapies,” Giedroc concluded.
Research article source: Daiana A. Capdevila, Joseph J. Braymer, Katherine A. Edmonds, Hongwei Wu, David P. Giedroc. Entropy redistribution controls allostery in a metalloregulatory protein. Proceedings of the National Academy of Sciences, 2017; 201620665 DOI: 10.1073/pnas.1620665114