Fig. 4.

Occupancy of MB ligands in the membrane-proximal binding pockets of the RPE65 cavity. Ligands are shown as van der Waals spheres with carbon, nitrogen, and oxygen atoms colored orange, blue, and red, respectively. (A) The cyclohexyl ring of emixustat resides close to a polar, water-filled pocket (blue arrow) within the membrane-proximal region of the active-site pocket. The bulkiness of the cyclohexyl moiety prevents it from occupying a nearby apolar pocket (red arrow) with the potential to promote ligand binding through hydrophobic and van der Waals forces. (B) One half of the MB-004 dipropyl moiety occupies the aforementioned hydrophobic cavity forming van der Waals contacts with residues lining the pocket, with the other half occupying a less constrained position near the active-site opening. (C) The binding pose for MB-008 is nearly identical to that of MB-004. Notably, the polar hydroxyl tail of MB-008 fails to form significant hydrogen bonding or dipolar interactions with residues or water molecules comprising the polar side of the proximal active-site pocket.