Extended Data Fig. 8: Ligand pocket prediction of two classic OR receptors.

We have used AlphaFold2 to predict the structure of mouse Olfr2 and Olfr78 and used the SiteMap algorithm to predict their corresponding ligand pockets. We then performed molecular docking and MD simulation to further probe the interaction between the octanal and propionate within the ligand pockets of their reported odorant receptors, the Olfr2 and Olfr78, respectively. a, Cut-away view of the ligand-binding pocket in the dopamine-D1R-Gs complex, (PDB:7CKZ, left), Octanal-Olfr2 complex generated by AlphaFold2 and MD simulation (middle) and MS47134-MRGPRX4-Gq (PDB:7S8P, right). b, Illustration of the Olfr2 and Olfr78 structures predicted by AlphaFold2. c, Predicted ligand-binding pockets in Olfr2 (left panel) and Olfr78 (right panel) determined using the SiteMap algorithm. The Olfr2 predicted binding pockets are filled with green, yellow, orange, cyan or blue balls. The Olfr78 predicted binding pockets are filled with red, green, pink, blue or cyan balls. d, The average RMSD value of octanal (upper panel) and key residues in Olfr2 that directly interact with octanal (lower panel) during triplicate 200 ns of MD simulation. e, The average RMSD value of propionate (upper panel) and key residues in Olfr78 that directly interact with propionate (lower panel) during triplicate 200 ns of MD simulation. f, Structural comparison of binding pocket of mTAAR9 with simulated structure of mouse octanal-Olfr2 and propionate Olfr78 which were generated by molecular docking based on the AlphaFold2 predicted structures of Olfr2 and Olfr78. The ligand pocket of both odorant receptors were defined by 4 helices, TM3-TM6. In contrast, the ligand pocket of mTAAR9 are defined by additional TM7, which potentially provide more interactions. Another notable difference is that the ligands of mTAAR9 binds deeper than those of predicted ligands within Olfr2 or Olfr78, forming direct contact with large hydrophobic residue W^6.48. In Olfr2 or Olfr78, the large hydrophobic residue W^6.48 was replaced by smaller residue Y^6.48, and don’t form direct contact with corresponding ligands.