Extended Data Fig. 4: Ligand binding pockets in DREADD and WT receptors.
From: Molecular basis for selective activation of DREADD-based chemogenetics
a, Side view of the binding pocket of the hM4Di-DCZ structure. Both DCZ and surrounding residues interacting with DCZ are shown in stick models. b, Interactions of the 8-chloro group of CNO with surrounding residues in the CNO-hM3Dq structure. The compound CNO is shown in both stick and sphere models and DCZ and surrounding residues are shown in the ball-and-stick model. c, Superposition of the binding pockets of hM3R-iperoxo, hM1R-iperoxo (6OIJ), and hM2R-iperoxo (6OIK) structures. The inset shows the structural comparison of the iperoxo molecules in the binding pockets of these three structures. Hydrogen bonds are indicated as dashed lines. d, Side view of the binding pockets of superposed hM3Dq-DCZ and hM3R-iperoxo structures. The deeper subpocket occupied by the heterocyclic group of iperoxo is formed by N3x37, V3x40, F5x47, W6x48, and N6x52. e-f, Structural comparisons of the hM3Dq-DCZ and rM3R-tiotropium (TIO, 4U15) structures (e), and the hM4Di-DCZ and hM2R-QNB (PDB: 3UON) structures (f). Major conformational differences of the TM4, TM5, and TM6 on the extracellular side and ligands are indicated by red and blue arrows, respectively. Ligands are shown in stick models. g, Interactions between DCZ or TIO and Y/C3x33, Y6x51, and N6x52 in hM3Dq or rM3R structure. The Y3x33 is shown in spheres. The conformational changes of the ligands and residues are indicated by gray and red arrows, respectively. h, Top view of the binding pocket comparison of predicted hM3R structure from the alphafold2 (AF2) server, modeled hM3Dq structure by alphafold2 server, and hM3R in the structure of the iperoxo-bound hM3R-miniGq complex.
