The mitochondrial F1Fo ATP synthase is responsible for the synthesis 90% of the ATP under aerobic conditions. The ATP synthase is a multimeric protein complex with an overall molecular weight greater than 550,000 Da. A portion of the ATP synthase is embedded in the mitochondrial membrane and acts as a proton turbine and a portion is in the matrix space and acts as a rotary engine that phosphorylates ADP. In the prior award period, we have solved the high resolution structures of 4 mutant forms of the F1 ATPase and determined the structural basis of mutations in F1 that uncouple proton translocation from ATP synthesis. The coupling of the ATP synthase is key to energy metabolism and yet the mechanism is poorly understood. We have also determined the high-resolution structures of the yeast c10-ring at pH 5.5, 6.1, 8.3, modified with DCCD, and bound with oligomycin. The current project builds upon our advances and expands our goals.
One aim of this project is to determine the high-resolution crystal structure of the ATP synthase complex from yeast S. cerevisiae.
This aim will give critical structural details into the understanding of the mechanism of proton translocation coupled to ATP synthesis. A number of genetic modifications will be used to facilitate crystallization of the entire complex. The high-resolution structure of the ATP synthase will provide the critical features to understand and treat diseases such as cancer and diabetes.

Public Health Relevance

The mitochondrial ATP synthase is an essential enzyme and involved in the energy conversion from carbohydrates, fats, and protein, to ATP, the energy form used by both human and bacterial cells. The efficiency of the enzyme is critical and drugs can act that modulate the efficiency or inactivate it, thereby killing the cells. For this reason, the ATP synthase is a good target for drugs that could control obesity, diabetes, cancer, and act as antibiotics and the studies in this project will provide new avenues for drug discovery.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Anderson, Vernon
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Rosalind Franklin University
Schools of Medicine
North Chicago
United States
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