Ligand-Olfactory Receptor Modelling

GPCRs are not unique to odour recognition. They also mediate the sense of vision, taste and pain. In addition, important cell recognition and communication processes often involve GPCRs, making them important targets for dmg development. Indeed, it was by analogy to these systems that the olfactory receptors were first discovered. 

There is evidence that the rat receptor (OR5) responds positively to Lyral and Lilial. Interestingly, both these materials are lily of the valley 

Ligand Receptor Putative binding site Reference 

Lyral OR5 Nine residues of helices 2-7. Tryptophan-278 in helix 7 forms H-bond with aldehyde group, 3 potential residues in helix 5 identified for binding to ligand hydroxy group. Leucine-245 in helix 6 and phenylalanine-104 in helix 3 forms van der Waal s interactions with cyclohexenyl moiety. Singer and Shepherd (1994b) 

Lyral OR5 Residues in helices 3, 4 and 5. Aspartic acid residue in helix 3 is important for H-bonding to OH of Lyral. Afshar et al (1998) 

---

In this model, OBPs participate in the selective transport of pheromone and other semiochemicals to their olfactory receptors. The selectivity of the system is likely to be achieved by layers of filters [ 16], i.e., by the participation of compartmentalized OBPs and olfactory receptors. It seems that OBPs transport only a subset of compounds that reach the pore tubules. Some of these compounds may not bind to the receptors compartmentalized in the particular sensilla. The odorant receptors, on the other hand, are activated by a subset of compounds, as indicated by studies in Drosophila, showing that a single OR is activated by multiple compounds [66]. If some potential receptor ligand reaches the pore tubules but are not transported by OBPs, receptor firing is prevented because the receptors are protected by the sensillar lymph. In other words, even if neither OBPs nor odorant receptors (ORs) are extremely specific, the detectors (olfactory system) can show remarkable selectivity if they function in a two-step filter. 

In a model borrowed from the study of bacterial chemotaxis, it was initially proposed that OBPs not only solubilize specific pheromones, but trigger the olfactory receptors when bound to odorant molecules (Pelosi, 1994). Later, it was further hypothesized that electrostatic and hydrophobic interactions from both the bound ligand and ligated protein are necessary and sufficient for receptor activation (Prestwich and Du, 1997). To the best of my knowledge the protein-ligand complex model has never been tested in bacteria. Certainly, it is not... 

Based on all evidence above, I propose the mode of action of OBPs follows the model depicted in Figure 15.8. OBPs participate in the selective transport of pheromones and other semiochemicals to their olfactory receptors. By selectivity, I do not mean that OBPs are the only filter of the olfactory system. In other words, I believe that OBPs may bind, solubilize, and transport structurally related ligands, but not compounds with unrelated chemical structures. This view is supported by the native gel-binding assay with BmPBP (Wojtasek and Leal, 1999) that showed binding to bombykol, but not to lactones, such as (R)- and... 

Singer MS,Shepherd GM. Molecular modelling off ligand-receptor interactions in the OR5 olfactory receptor. NeuroReport 1994 5 1297-1300. 

---