Structural studies of macromolecules
Our work on ATP synthase, in collaboration with Sir John Walker (MRC Mitochondrial Biology Unit) aims to determine the structure of this energy-transducing complex from mitochondria. It is a complex structure of sixteen different polypeptides with a total molecular weight of over 500,000 Da. We have determined the structure of the catalytic sector (F1-ATPase) in a variety of different states. The structures of an F1c10 subcomplex of the yeast ATP synthase, a three-subunit complex of the peripheral stalk, and the NMR structure of another component of the peripheral stalk (the OSCP protein), have been assembled within a cryo-EM derived envelope to provide a model of the whole enzyme. We are now focusing on obtaining high quality crystals of the complete enzyme. We hope that the structure will help us to understand the mechanism that couples proton transport to ATP synthesis.
We are also working on integral membrane proteins, a wide variety of which perform crucial activities in living cells. In collaboration with Chris Tate, we are studying the atomic structures of membrane proteins that are specifically involved in signalling and transport. This includes the G-protein coupled receptors β1-adrenergic receptor and the adenosine A2A receptor.
We are also developing software (MOSFLM) for processing X-ray diffraction data. Recently this has focussed on a new graphical user interface (GUI) and developments that will allow more automated data collection and processing, especially at synchrotron beamlines. We will be enhancing the algorithms employed by MOSFLM to be able to tackle more challenging problems (such as very weak diffraction, multiple lattices, high mosaicity) as well as optimising processing of images from the new generation of pixel detectors.
- Lebon, G., Warne, T., Edwards, P.C., Bennett, K., Langmead, C.J., Leslie, A.G.W. and Tate, C.G. (2011)
Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation.
Nature 474: 510-514.
- Warne, T., Moukhametzianov, R., Baker, J.G., Nehme, R., Edwards, P.C., Leslie, A.G.W., Schertler, G.F.X. and Tate, C.G. (2011)
The structural basis for agonist and partial agonist action on a β1-adrenergic receptor.
Nature 469: 241-244.
- Moukhametzianov, R., Warne, T., Edwards, P.C., Serrano-Vega, M.J., Leslie, A.G.W., Tate, C.G. and Schertler, G.F.X. (2011)
Two distinct conformations of helix 6 observed in antagonist-bound structures of a β1 adrenergic receptor.
Proc Natl Acad Sci 108: 8228-8232.
- Battye, T.G.T., Kontogiannis, L., Johnson, O., Powell, H.R. and Leslie, A.G.W. (2011)
iMosflm: a new graphical interface for diffraction image processing with MOSFLM.
Acta Cryst D67: 271-281.
- Rees, D.M., Leslie, A.G.W. and Walker, J.E. (2009)
The structure of the membrane extrinsic region of bovine ATP synthase.
Proc Natl Acad Sci 106: 21597-21601.
- Harry Powell
- Minmin Yu