FIGURE 9.

Preferred binding mode for the functionally biased agonist wFw-Isn-NH₂ in the main ligand-binding pocket of the ghrelin receptor compared with the wFwLL compound. Rosetta-based molecular modeling and docking was performed as described under “Experimental Procedures.” A, the preferred C-out docking mode for the L-shaped wFw-Isn-NH₂ ligand (in green) in the main ligand-binding pocket between TMs III, VI, and VII of the ghrelin receptor as viewed from the side (from TM VII). B, the same docking mode as in A but viewed from TM IV. C, the same docking mode as in A but viewed from the extracellular space. Note the interaction of the important C-terminal carboxyamide group, especially with Arg¹⁹⁸ in ECL-2b; the aromatic-aromatic interaction of the wFw motif with the aromatic cluster, for example PheVII:06, PheVI:16, and PheVI:23; and the lack of interaction with GluIII:09 in this docking mode. D and E, the C-in docking mode of the structurally closely related and also L-shaped wFwLL ligand in the same binding pocket between TMs III, VI, and VII. Note that the ligand docks in the opposite mode with the C-terminal carboxyamide closely interacting with GluIII:09, the free N-terminal NH₂ group at the receptor surface leaving free space for various N-terminal extensions, and the wFw aromatic motif interacting with the aromatic cluster between TMs VI and VII but in a different mode than the wFw-Isn-NH₂ ligand.