Structure of GPCR Signalling complexes Gebhard F. X. Schertler
MRC Laboratory of Molecular Biology G protein-coupled receptors comprise the largest gene family in the human genome. They are central to neurobiology, pharmacology and sensory physiology. The visual system is by far the best-studied system at the molecular level and at the level of brain organisation. Working at the molecular level, we have determined the structure of rhodopsin by X-ray crystallography and electron microscopy. Our structures have important new implications for the G protein-binding surface of unactivated rhodopsin. Recently we have solved the structure of the stress hormone receptor beta1 and beta 2 adrenergic receptor. The most important question left in the field is the molecular mechanism of G protein-coupled receptor activation. For this we will need the structure of the activated receptor in complex with other signalling molecules. We will therefore developed biochemical protocols to isolate Receptor/transducin and receptor/arrestin complexes using native and recombinant proteins and will crystallise these signalling complexes. In contrast to other systems, the components of the visual system are well characterised and available from native sources as well as expression systems. We will crystallise the signalling complexes and solve their structure with the most advanced X-ray and electron microscopy techniques available. >From these structures we will gain insight into the general activation mechanism of G protein-coupled receptors. This mechanism is of crucial importance for the regulation of neurobiological processes and it might give new possibilities for pharmacological intervention. Warne,T, Serrano-Vega, M. J., Baker, J. G., Moukhametzianov, R,, Edwards, P. C., Henderson,R , Leslie, A. G.W., Tate, C. G. & Schertler, G. F.X.. (2008). Structure of a beta-1 adrenergic G-protein-coupled receptor. Nature 454, 486-491 Schertler, G. F.X..(2008). Signal Transduction: The rhodopsin story continued. Nature 453, 292-293 Kobilka, B. & Schertler, G. F. (2008). New G-protein-coupled receptor crystal structures: insights and limitations. Trends Pharmacol Sci. 29, 79-83 Moukhametzianov, R., Burghammer, M., Edwards, P. C., Petitdemange, S., Popov, D., Fransen, M., McMullan, G., Schertler, G. F. & Riekel, C. (2008). Protein crystallography with a micrometre-sized synchrotron-radiation beam. Acta Crystallogr D Biol Crystallogr 64, 158-66. Søren G. F. Rasmussen1, Hee-Jung Choi1, Daniel M. Rosenbaum, Tong Sun Kobilka, Foon Sun Thian, Patricia C. Edwards, Manfred Burghammer, Venkata R. P. Ratnala1, Ruslan Sanishvili, Robert Fischetti, Gebhard F. X. Schertler, William I. Weis1, and Brian Kobilka1 (2007). Crystal structure of the human beta 2 adrenoceptor. Nature 450, 383-387 Jörg Standfuss, Guifu Xie, Patricia Edwards, Manfred Burghammer, Daniel D. Oprian and Gebhard F. X. Schertler (2007). Crystal Structure of a Thermally Stable Rhodopsin Mutant. J Mol Biol 372, 1179-1188 Please apply online and copy to my e-mail: [EMAIL PROTECTED] http://www2.mrc-lmb.cam.ac.uk/projects/PhD_Programme.html Postgraduate Office, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. Email: [EMAIL PROTECTED] Tel: +44 (0)1223 402262 Fax: +44 (0)1223 412142 -------------------------------------------- Dr. Gebhard F. X. Schertler Senior Scientist and Group Leader MRC Laboratory of Molecular Biology Hills Road Cambridge CB2 0QH UK tel 0044 1223 402328 fax 0044 1223 213556 e-mail [EMAIL PROTECTED] web http://www2.mrc-lmb.cam.ac.uk/SS/Schertler_G/
