Structure of activated states of G protein-coupled receptors by electron cryo-microscopy
Group Leader page
The structures of G protein-coupled receptors in multiple different conformations are necessary to understand how agonists activate the receptor to facilitate G protein coupling. In addition, structures are also required bound to arrestins to understand the molecular mechanism of biased agonism. We have developed a thermostabilisation technology that has allowed us to determine the structures of multiple different GPCRs bound to inverse agonists, partial agonists, biased agonists and full agonists. Recently, we also developed a thermostabilised G protein that has allowed us to determine the structure of the activated state of the adenosine A2A receptor. We wish to build on these successes and to utilise the developments in electron cryo-microscopy to determine structures of GPCRs bound to stabilised heterotrimeric G proteins and arrestin by single particle imaging.
The successful candidate will be expected to learn all the steps involved in the overexpression, purification and preparation of cryo-EM samples of a GPCR and to determine one or more structures using the Titan Krios equipped with state of the art detectors. The candidate will join a team of experts studying all aspects of GPCR structure and biochemistry, and will also be expected to collaborate with experts in cryo-EM (Sjors Scheres group).
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Agonist-bound structures of the adenosine A2A reveals common features of GPCR activation.
Nature 474, 521-525.
Warne et al. (2011)
The structural basis for agonist and partial agonist action on a b1-adrenergic receptor.
Nature 469, 241-244
Carpenter et al. (2016)
Structure of the adenosine A2A receptor bound to an engineered G protein.
Nature. DOI 10.1038/nature18966