Products Cited in Publications Worldwide Structure, Dynamics, and Therapeutic Potential of ATP Synthase

Structure, Dynamics, and Therapeutic Potential of ATP Synthase

Guo, Hui

Abstract

Found in mitochondria, chloroplasts, and bacteria, ATP synthases are rotary enzymes that use energy from respiration to generate adenosine triphosphate (ATP). The dumbbell-shaped macromolecular complex consists of a soluble F1 motor and a membraneembedded FO motor connected by a shared central rotor. Studying the molecular mechanism of both motors and how they are coupled together to form a functional enzyme is critical for understanding bioenergetics and respiration. In this thesis, single particle electron cryomicroscopy (cryoEM) was employed to investigate the structure, dynamics, and therapeutic potential of ATP synthase. To improve cryoEM sample preparation and data storage, a grid freezing device and a movie storage file format were developed. Highresolution structures of both mitochondrial and bacterial ATP synthases demonstrate how proton translocation across the membrane via two proton half channels in the FO region drives rotation of the rotor. The dimeric mitochondrial ATP synthase structure also explains how the enzyme forms dimers, bends the mitochondrial inner membrane, and iii produces cristae—the characteristic structure of mitochondria. Structures of ATP synthase during rotary catalysis illustrate how the enzyme deforms under strain to achieve efficient coupling of the F1 and FO motors. Additionally, structures of ATP synthases bound to the tuberculosis drug bedaquiline and the antileukemia compound apoptolidin highlight the potential of ATP synthase as drug targets for treatment of bacterial infection and respiration-dependant cancer. Together, our results uncovered fundamental mechanisms that enable function of this fascinating molecular machine and explored how medicines targeting the enzyme might be harnessed to benefit human health.

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Bedaquiline

A193466843663-66-199%

Bedaquiline

36.0/2mg

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