The new study led by the team of researchers of Rosalind Franklin University of Medicine and Science has resolved the structure of enzyme which makes ATP i.e. mitochondrial ATP synthase structure. This research lifted the barrier to understanding their function in disease and drug mechanisms.
ATP synthase is an enzyme that produces the energy storage molecule adenosine triphosphate (ATP). As ATP synthase has a major role in fueling the cell, determining the complete structure of this enzyme holds a promising key to many secrets about the ATP machine. Knowing the Structure of ATP machine can help in identifying the therapeutic target and advance understanding of a metabolic disease and other cellular pathologies.
“Understanding how the enzyme actually works requires the knowledge of its three-dimensional molecular structure at the atomic level,” said Dr. Professor David M. Mueller, principal investigator for the study that used cryo-electron microscopy (cryo-EM) to reveal the enzyme at near atomic resolution.
In oxidative phosphorylation, Oligomycin A is an inhibitor of ATP synthase. Therefore, the complete structure of ATP synthase provides evidence for the mechanism by which the oligomycin inhibits the enzyme. This study can also help in studying how disease-causing mutations disrupt the function of the molecule. The function of ATP synthase in disease and drug mechanisms can be understood in a broader way after solving the structure of ATP synthase.
The study was published in the journal Science which covers the method by which structures of other functional states of the ATP synthase was determined. This enzyme has been the subject of structural studies for decades in labs across the globe.
Dr. Mueller who is an investigator in the university’s Center for Genetic Disease took a collaborated with scientists from the National Institutes of Health and a team at Harvard University and applied a different approach for resolving the structure.They used cryo-EM analysis to decipher the engineered ATP synthase, which was synthesized in yeast and reconstituted into nanodiscs to allow for structural analysis. While cryo-EM isn’t new, advancements in technology have made it possible to solve the structure at near atomic resolution.
“This study illustrates how a coordinated effort by scientists can bring about an important goal,” Dr. Mueller said. “None of us were looking at this project from our own particular point of view. We were focused on the goal itself. Through collaboration, we solved a problem that individually, we couldn’t.”