Crystal structure of a beta-adrenergic receptor with bound ligand

The Project challenge

Membrane receptors are difficult to work with, and their purification and crystallisation are particularly laborious. The fragile nature of the resulting crystals make data collection an enormous challenge.

Background

G-Protein Coupled Receptors (GPCRs) are the conduit for almost all the transmembrane signal transduction that occurs in response to hormones and neurotransmitters. They are of enormous interest due to their diverse physiological roles and potential as drug targets. The β2-adrenergic receptor is involved in the body’s fight or flight response, it acts in response to adrenaline. Crystal structures are crucial in the understanding of how hormone binding leads to signal transduction and to investigate the binding of potential therapeutic drugs.

Results

Data collected at the ESRF microfocus beamlines ID23-2 and ID13 led to the solution of the first structure of the human member of this family, the β2-adrenergic receptors.

How did the synchrotron help ?

Small poor quality crystals needed a high intensity microfocus beam to obtain the best data. Many crystals were screened. Data were collected by probing different parts of the same crystal.

The Future

The pioneering working in producing these membrane protein crystals and the routine use of microbeam techniques will allow further study and design of new drugs with higher specificity, which means that they will have fewer side-effects.

Figure 1. The crystal structure of the human β2-adrenergic receptor. The seven transmembrane helices are shown as cylinders (coloured in a rainbow from the N- to C-terminus of the protein. Its position within a lipid bilayer is illustrated.

Further information

• S.G.F. Rasmussen, H.-J. Choi, D.M. Rosenbaum, T.S. Kobilka, F.S. Thian, P.C. Edwards, M. Burghammer, V.R.P. Ratnala, R. Sanishvili, R.F. Fischetti, G.F.X. Schertler, W.I. Weis and B.K. Kobilka, Crystal structure of the human β2 adrenergic G-protein-coupled receptor, Nature 450, 383 (2007).
• T. Warne, M.J. Serrano-Vega, J.G. Baker, R. Moukhametzianov, P.C. Edwards, R. Henderson, A.G.W. Leslie, C.G. Tate, G.F.X. Schertler, Structure of a β1-adrenergic G-protein-coupled receptor, Nature 454, 486 (2008).