The largest movement during activation of G protein-coupled receptors (GPCRs) involves TM6. Viewed from the intracellular end, TM6 pivots outwards and rotates clockwise; this 'macroswitch' occurs in all GPCRs studied to date . This shift is markedly different in the BU72-μOR-Nb39 structure than in later structures of active μOR bound to Gi protein (Figure and Table ). Although these 13 later structures feature diverse µ opioids bound to mouse or human μOR, they cluster very tightly in this key region. The BU72-bound structure is a clear outlier, with TM6 much closer to TM5, and rotated in the opposite direction. As a result, intracellular loop 3 (ICL3) bunches outwards in a disordered loop, rather than being pulled into a helix as in the Gi-bound structures. These differences appear to be largely due to Nb39, since the structure of the κ opioid receptor (κOR) bound to the same nanobody is similar (Figure ).