Structure determination of integral membrane proteins
Integral membrane proteins are fundamental to a cells survival, allowing the import of nutrients, the export of toxins and intercellular communication via receptors. We aim to understand the processes of solute translocation and receptor signalling processes by determining the structures of important and interesting membrane proteins by x-ray crystallography. Particular focuses of the lab are G protein-coupled receptors (GPCRs), neurotransmitter transporters and bacterial multidrug transporters.
There are over 350 non-odorant GPCRs encoded by the human genome that are involved in hormone binding and transducing this signal to the cytoplasm, resulting in the activation of G protein pathways and eventually eliciting a cellular response. The key role of GPCRs in signal transduction pathways makes them ideal as drug targets with many classes of small molecule drugs, such as beta blockers or anti-asthma treatments, either inhibiting or activating these receptors. There are many potential problems in determining the structure of membrane proteins, but we have developed a strategy based on rational mutagenesis to improve the thermostability of GPCRs, which has made crystallisation and structure determination far more tractable. We have now determined multiple structures of the β1 adrenergic receptor, adenosine A2A receptor and neurotensin receptor bound either to full agonists, partial agonists, inverse agonists or biased agonists.
- White, J.F., Noinaj, N., Shibata, Y., Love, J., Kloss, B., Xu, F., Gvozdenovic-Jeremic, J., Shah, P., Shiloach, J., Tate, C.G. and Grisshammer, R. (2012)
Structure of the agonist-bound neurotensin receptor
Nature 490: 508-513
- Warne, T., Moukhametzianov, R., Baker, J.G., Nehme, R., Edwards, P.C., Henderson, R., 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.
- Lebon, G., Warne, T., Edwards, P.C., Bennett, K., Langmead, C.J., Leslie A.G.W. and Tate C.G. (2011)
Agonist-bound structures of the adenosine A2A reveals common features of GPCR activation.
Nature 474: 521-525.
- Pat Edwards
- Javier Garcia-Nafria
- Jonna Hakulinen
- Lukas Helfinger
- Yang Lee
- Jade Li
- Maki Ohashi
- Ankita Singhal
- Annette Strege
- Antony Warne