Fig. 6: Comparable accommodation of GABOB enantiomers in the orthosteric site.
From: Cryo-EM structures of ρ1 GABAA receptors with antagonist and agonist drugs
a Refinement of (R)- (tan) and (S)-GABOB (cyan) into ligand density in the partially-locked state of ρ1-EM (purple), colored by heteroatom. b Refinement of (R)- and (S)-GABOB into ligand density in the desensitized state of ρ1-EM (blue), otherwise colored as in (a). c Protein-ligand interactions of (R)- and (S)-GABOB in the partially-locked state of ρ1-EM, colored as in (a). d Protein-ligand interactions of (R)- and (S)-GABOB in the desensitized state of ρ1-EM, colored as in (b). e Schematics of (R)- (left, tan) and (S)-GABOB (right, cyan) interactions with the partially-locked state of ρ1-EM. f Schematics of (R)- (left, tan) and (S)-GABOB (right, cyan) interactions with the desensitized state of ρ1-EM. In (e, f), hydrogen bonds and other electrostatic interactions are indicated as dashed lines, hydrophobic and aromatic interactions as lashes. g Mobility of (R)- and (S)-GABOB in MD simulations of ρ1-EM in the partially-locked (left, purple) and desensitized states (right, blue), as quantified by ligand RMSD (Å). Violin plots represent probability densities from 4 independent simulation replicates, sampled every 0.4 ns for the first 400 ns of each replicate (n = 4000), with markers indicating median and extrema. h Zoomed view of the orthosteric ligand site in resting (green), partially-locked (purple) and desensitized states (blue). Labels indicate the distance between nearest heavy atoms of Y268 and R179(-), where an apparent hydrogen bond characterizes ligand-bound versus -unbound states. i Distance between the Y268 hydroxyl and R179(-) guanidinium groups in MD simulations of ρ1-EM with (R)- and (S)-GABOB in the partially-locked (left, purple) and desensitized states (right, blue). Violin plots represent probability densities from 4 independent simulation replicates, sampled every 0.4 ns for the first 400 ns of each replicate (n = 4000), with markers indicating median and extrema. Dashed lines indicate static distances in the resting (green) and desensitized (blue) structures.
