Tertiary structure modelling of active G protein coupled receptor states

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G protein coupled receptors (GPCRs) transduce extracellular signals into the cell through activation of intracellular G proteins (G) or arrestins (Arr). High resolution structures of currently 25 different inactive receptor states reveal a common topology of transmembrane helices (TM) even of distantly related GPCRs. The topology of the inactive state is even preserved in X-ray structures of agonist bound receptors. Only in co-crystals of GPCRs with G or Arr or mimicking proteins or fragments, the receptor exhibits the active state conformation (R*), which hallmarks are rearrangements of TM5 and 7 and outward tilting of TM6. By contrast, recent nuclear magnetic resonance spectroscopy and molecular dynamics simulations reveal that the R* samples several conformational states and substates in the absence of G or Arr. The states selected for specific binding of G or Arr are already present within the conformational space of the prototypical photoreceptor rhodopsin or the beta2-adrenoceptor. To elucidate the conformational space of R* states of other members of the large super-family of GPCRs and to model their interactions with G or Arr, computational biophysics and bioinformatics approaches will be combined here. We will develop and apply novel computational tools e.g. to investigate the role of water mediated hydrogen bonding networks and receptor voids for activation and biased signalling. The principle objective of this project is to elucidate the key determinants for differential interactions of the large GPCR super-family with G or Arr, eventually modulating the receptors' efficacy to activate different downstream signalling pathways.