Chris Tate

Structure determination of integral membrane proteins
Personal group site

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.

The structure of the thermostabilised β1-adrenergic receptor, β1AR-m23 [1] is shown in rainbow colouration (N-terminus blue, C-terminus red). The positions of the thermostablising mutations are shown as space-filling models of the relevant side chains (magenta, mutations in m23; grey, other thermostabilising mutations). The antagonist cyanopindolol and the Na+ ion are also shown as space filling models.

Structure of β1AR-m23 bound to the agonist carmoterol used in the treatment of asthma and chronic obstructive pulmonary disease.

Selected Papers

Group Members

  • Pat Edwards
  • Jade Li
  • Antony Warne
  • Rony Nehme
  • Javier Garcia-Nafria
  • Maki Ohashi
  • Yang Lee
  • Ankita Singhal
  • Annette Strege
  • Jonna Hakulinen
  • Olivier Lan Chow Wing