Fig. 6: Mechanism of Y₁R activation by NPY binding.

Schematic figures representing antagonist-bound (left) and NPY-bound (right) Y₁R are shown. Two key regions for Y₁R activation are indicated by dashed ellipses. The three phenylalanine residues at TM6 and TM7, and Q120^3.32, I128^3.40, P223^5.50, and F272^6.44 in the connector region are shown in stick representation. The three phenylalanine residues participate in antagonist binding through π–π interactions, but these interactions are rearranged upon NPY binding. F286^6.58 flips and forms a new interaction network with Y1 and R33 of NPY. Since F286^6.58 is not conserved in Y₂R, F286^6.58-mediated interactions are Y₁R-selective. Q120^3.32, I128^3.40 and F272^6.44 show rotamer changes upon NPY binding. A series of these changes upon NPY binding pulls TM3 upward and causes outward movement of the cytoplasmic region of TM6.