ATP synthase: a Bio-Molecular Power Station

We study energy conversion by a bio-molecular power station the enzyme ATP synthase. This enzyme provides our body (and bacteria, plants and animals) with the universal energy currency of life, a compound called ATP.

The enzyme is a highly unusual machine: one part, referred to as Fo, works like an electro-motor: When protons (H+ in Figure 1) move as indicated by the black arrow, the reddish part of the enzyme rotates. Another part of the enzyme, called F1 acts like no machine ever build by man: mechanical energy (rotation) is used to synthesize a chemical compound (ATP).      

It is possible to remove the F1 part from ATP synthase. F1 alone splits ATP leading to rotation of the g part, thus working as a combustion engine  (Figure 2). As the enzyme is too small to be observed directly, a large probe (red ball in Figure 2) is attached to the rotating g part and observed by optical microscopy. We succeeded in manipulating the speed of the rotation by addition of an external chemical signal (oxidation-reduction, antibiotic inhibition, illumination). Presently, we attempt to combine this motor with other (motor-) units to build more complex supra-molecular structures. 

ATP synthase is the target for several antibiotics, plays a role in providing energy for cancer cells and is reported to be involved in cholesterol metabolism. Using Surface Plasmon Resonance Sensing (Biacore) we demonstrated that diarylquinoline (DARQ), a highly promising drug-candidate for treatment of tuberculosis, binds to ATP synthase, interrupting its function (Figure 3). Using biochemical, proteomic and spectroscopic methods (FRET etc.) we plan to examine how the enzyme responds to these stimuli and how e.g. an antibiotic influences ATP synthase and ATP levels in the context of the whole cell.

Contact: Dr. Dirk Bald, e-mail: dirk.bald@falw.vu.nl
Structural Biology
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Figure 1: Overview of ATP synthase
Figure 2: A. Method used to observerotation of F1.  B. Control ofrotation: fast (Row 1), slow(Row 2) and again fast (Row 3).
Figure 3: ATP synthase binds to anantibiotic (DARQ) immobilizedon a CM5 Biacore chip, but notto the empty chip (crosses).