Figure 9
D2AAK1 binding sites identified in 5-HT2A receptor. (A) The allosteric site is located at the top of TM6 and TM7 and involves several polar interactions with aspartate and glutamate residues, as well as non-polar interactions and notable shape complementarity of the methoxyindole moiety and a small pocket under ECL3. (B) FES of D2AAK1 binding to 5HT2AR with its two apparent basins: one at the distance of ca. 2.5 nm, corresponding to the pocket shown in the panel (A), and the one at the distance of ca. 1.1 nm, corresponding to the orthosteric binding as shown in the panel (C). (C) D2AAK1 binds in the orthosteric pocket of 5HT2AR in a manner resembling methiothepin, as seen in the 6WH4 PDB structure, preventing W6.48 motility. Simulations in explicit solvent enabled identification of water-mediated interactions with S5.43.
