Binding sites in MR crystal structures. (A) Orthosteric sites for tiotropium in the crystal structures of tiotropium-bound M1R (top left, Supplemental Material 1-PDB ID 5CXV), M3R (bottom right, Supplemental Material 1-PDB ID 4DAJ), and M4R (top right, Supplemental Material 1-PDB ID 5DSG), and the orthosteric site for QNB in the crystal structure of M2R (bottom left, Supplemental Material 1-PDB ID 3UON). Polar interactions are shown as dashed lines. (B) Crystal structure of active M2R with the orthosteric agonist iperoxo only (left, Supplemental Material 1-PDB ID 4MQS, allosteric site empty) and crystal structure of active M2R with iperoxo and a PAM named LY2119620 (right, Supplemental Material 1-PDB ID 4MQT). Full agonist iperoxo is in the orthosteric site of both structures.