The last 10 years has seen a huge increase in the numbers of X-ray structures solved for GPCRs. However solving fully active structures in complex with G proteins remains challenging. Recent advances in cryo-electron microscopy (cryo-EM), including improved direct electron detectors and image processing methods, mean that near atomic resolution is becoming possible for protein complexes of smaller molecular size (sub 100kDa). Cryo-EM has the advantage over X-ray crystallography in that structures are determined from single molecules, avoiding the need to grow crystals (although sample preparation is still not trivial). This is particularly useful for large macromolecular complexes or proteins with labile domains which are difficult to crystallize. A dramatic step up in quality of data collected has been achieved using the volta phase plate which greatly increases the contrast, particularly at the lower end of the molecular size range, meaning that structures of GPCR complexes are now within reach. The first example of this has been published in Nature by the groups of Patrick Sexton at Monash and Wolfgang Baumeister at the Max Planck in Martinsried. Using the volta phase plate the cryo-EM structure of the full length calcitonin receptor bound to a peptide agonist in complex with the heterotrimeric G protein was solved to 3.8 Ä. The structure reveals the conformational changes which occur upon activation of a Class B GPCR. Cryo-EM is set to revolutionise structural biology and with the rapid progress is now encompassing GPCR complexes. We expect others to follow in the near future.
 Liang et al. (2017). Phase-plate cryo-EM structure of a class B GPCR–G-protein complex. Nature, doi: 10.1038/nature22327. [PMID: 28437792]
Comments by Dr. Fiona H. Marshall (Director & CSO, Heptares Therapeutics) (@aston_fm)