Fig. 4: Comparison of binding mode between NPY and antagonists.

a Ligand-binding site occupied by UR-MK299 (PDB ID 5ZBQ, magenta) and b BMS-193885 (PDB ID 5ZBH, slate) is compared with the binding site for NPY (yellow). The side chains of Q219^5.46 are differently oriented in all three structures, whereas D287^6.59 and T212^5.39 maintain similar interactions. c Q120^3.32-mediated interactions in the antagonist-bound and NPY-bound structures are compared. In the NPY-bound active structure of Y₁R, TM3 including Q120^3.32 shifts upward and Q120^3.32 forms a polar interaction with the C-terminal amide of NPY through its upward-facing sidechain. d Upon NPY binding, F286^6.58 rotamer is changed to form the interactions with NPY R33, L30, and Y1. e Upon NPY binding, I293^ECL3 participates in a hydrophobic interaction network with F286^6.58, H298^7.31, and F302^7.35. UR-MK299-bound Y₁R is indicated in light gray, and BMS-193885-bound Y₁R is in pink. Red arrows represent positional changes of I293^ECL3 and F286^6.58 upon NPY binding.