Possible mechanism for OR51E2 activation by ionones.

[primaryodors]

Making the following changes to the cryo-EM model, it should be possible to correctly predict α- and β-ionone, and δ-decalactone, as agonists using a theoretical alternative active configuration:

• Bend the EXR portions of TMR4 and TMR5 outward somewhat;
• Back-pivot TMR6 so that Ser258 is 1-2A farther from Gln181;
• Repoint Arg262's side chain away from the binding pocket.

Larger chain (6+ carbon) fatty acids will not fit in the expanded binding pocket, which will be inflated slightly but not lengthened. It will be important to identify which internal contacts differ between the cryo-EM model and the theoretical alternative model.

See attached video clip of β-ionone nearly fitting the active binding pocket except for a few clashes.

https://github.com/primaryodors/primarydock/assets/106125032/5ba0c51c-226f-47c8-b4bc-d902c7ec3a7f

[primaryodors]

The dock of OR2M3 with its primary agonist supports the idea that the EXR portions of TMR4, TMR5, and TMR6 may bend outward slightly to accommodate a ligand. In so doing, they lose a small amount of contact with nearby helices, but if the energy favorability gained by contact with the ligand outweighs the energy favorability lost by decreasing interhelical contact, then the overall energy favors the ligand in that pose.