Structural variation and odorant binding for olfactory receptors selected from the six major subclasses of the OR phylogenetic tree

To provide some insight on odorant recognition, we partitioned the 398 human olfactory receptors (OR) into six subclasses based on the phylogenetic tree and predicted the 3D structure and binding site for the family head of each subclass. We used the GPCR Ensemble of Structures in Membrane BiLayer Environment (GEnSeMBLE) method that samples 10 trillion combinations of helix tilts and rotations to select an ensemble of the 25 most stable 7-helix packings. We found that the ensembles for the OR in all 6 subclasses exhibit the TM1-2-7 coupling characteristic of Class A G protein-coupled receptors (GPCRs). In many cases of tetrapod subclasses, the conserved R3.50:E6.30 TM3-TM6 coupling in the inactive GPCRs is replaced with D(E)3.39:H6.40 and D3.49:R(K)6.30 interactions. We found a different pattern for the fish-like class I, where D3.49 couples with residues in TM4 (R4.44 for O52D1-I and Q4.41/K4.38 for O52B6-I) instead of TM6. A variety of residues lining the binding site are involved depending on the ligand: Q103^3.28 and N282^7.39 for O52D1-I, Y91^2.53 for O11H6-II, Q97^3.28 for OR4Q2-III, S272^7.35 for OR7D4-IV, S206^5.43 for OR2J3-V, and T249^6.45 for OR5P3-VI. Here, we provide the structures for the top25 for all 11 ORs, including the structures with ligands.