Fig. 2: Ligand-binding pocket of active HCAR2 bound to different agonists.

a Chemical structures of niacin, acipimox, and MK-6892. b Vertical cross-sections of the binding pockets of niacin, acipimox, and MK-6892 in HCAR2. c–e Detailed interactions of niacin, acipimox and MK-6892 with HCAR2. The polar interactions are indicated by dark gray dashed lines. f Superposition of the niacin, acipimox, and MK-6892 binding poses, as well as surrounding key residues. g General pharmacophore features common to most of the agonists recognized by HCAR2. The structures of HCAR2 and agonists are colored differently. Forest green, niacin–HCAR2; deep sky blue, acipimox–HCAR2; hot pink, MK-6892–HCAR2; blue purple, N-terminal loop; light green, ECL1; sky blue, ECL2; coral, ECL3; yellow, niacin; dark orange, acipimox; cyan, MK-6892. h–j Effects on Gi-mediated cAMP by single-point mutations of R111^3.36, Y284^7.43, S179^45.52, and Q112^3.37 that interact with niacin, acipimox, and MK-6892. The data are presented as mean ± SEM. The experiments were performed in triplicate.