State-dependent protein-lipid interactions of a pentameric ligand-gated ion channel in a neuronal membrane
Fig 6
Overlay of cholesterol density with positive allosteric modulator ivermectin at the subunit interface and corresponding binding poses from atomistic simulations.
A Overlay of the human α1 GlyR model (darker colours) and cholesterol density (transparent, hydroxy group density in red, remaining hydrophobic steroid skeleton in cyan) from simulations in the active state with the currently highest resolution crystal structure of human α3 GlyR (PDB 5VDH) (lighter colours) with ivermectin (green) bound. Shown is the ivermectin binding site at the interface of adjacent subunits with the (+)M2 and (+)M3 helices of the principal subunit (orange) and the (-)M1 helix of the complementary subunit (purple) forming a crevice and the (+)M2-M3 linker acting as a lid towards the extracellular side. Ivermectin and important residues for ivermectin or cholesterol binding are shown explicitly and key interactions are highlighted by black lines. B Representative snapshot of cholesterol binding poses from fully atomistic MD simulations that overlay well with the density observed in CG MD simulations, illustrating that an ensemble of 3 cholesterol molecules can simultaneously interact at this site.