Olfactory Receptor Modelling

Doszczak L, Kraft P, Weber H-P, Bertermann R, Triller A, Hatt H, Tacke R. Prediction of perception probing the hOR17-4 olfactory receptor model with silicon analogues of bourgeonal and lilial. Angew. Chem. Internal. Ed. 2007 46 3367-3371. 

Afshar M., Hubbard R. and Demaille J. (1998). Towards structural models of molecular recognition in olfactory receptors. Biochimie 80, 129-135. 

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... 

Recently, a putative olfactory receptor from Drosophila, Or43a (Clyne et al., 1999 Vosshall et al., 1999), has been expressed in Xenopus laevis oocytes (Wetzel et al., 2001). The receptor expressed in a heterologous cell system was activated by four odorants, i.e. cyclohexanone, cyclohexanol, benzaldehyde, and benzyl alcohol (Wetzel et al., 2001). These experiments not only provided direct evidence for the function of the Or gene, but also demonstrated that the olfactory receptor can be stimulated without an odorant-binding protein. It was demonstrated earlier that PBP was not necessary to obtain pheromone-dependent responses in cultured olfactory receptor neurons of Manduca sexta (Stengl et al., 1992). The possibility that OBPs have been produced in vitro and were present in cultured ORNs could not be excluded. The same argument can not be raised for the heterologous expression of the Drosophila olfactory receptor. While the evidence that Xenopus oocytes responded to odorants in the absence of OBPs does not support the OBP-odorant complex model, it also demonstrated that OBPs are essential for the kinetics of the olfactory system (see below). 

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... 

Merrill C. E., Riesgo-Escovar J. R., Pitts R. J., Kafatos F. C., Carlson J. R. and Zwiebel L. J. (2002) Visual arrestins in olfactory pathways of Drosophila and the malaria vector mosquito Anopheles gambiae. Proc. Natl. Acad. Sci. USA 99, 1633-1638. Moore P. A. (1994) A model of the role of adaptation and disadaptation in olfactory receptor neurons implications for the coding of temporal and intensity patterns in odor signals. Chem. Senses 19, 71-86. 

For various reasons, it is very difficult to develop an understanding of the chemistry involved in olfaction. The olfactory receptors are found in the membrane of the receptor cells therefore, their active states are not amenable to structural determination by X-ray diffraction or other physical tools. Odor is a mental image rather than a physical property that can be measured and quantified. Odor perception is a multistep process. Olfaction is combinatorial in nature. All of these facts indicate that building of either substrate or receptor models are fraught with significant difficulties. 

The structure/activity relationship (SAR) tools employed in odor research are essentially the same standard tools used in all applications, and the models developed fall into the categories of substrate and receptor models. The pharmaceutical industry is the leader in SAR techniques, and the fragrance industry tends to follow its lead. Early models were substrate based, but the discovery of the genes that code for the olfactory receptor proteins has also allowed receptor models to be constructed. 

Pilpel Y, Lancet D. The variable and conserved interfaces of modeled olfactory receptor proteins. Protein Sci. 1999 8 969-977. Man O, Gilad Y, Lancet D. Prediction of the odorant binding site of olfactory receptor proteins by human-mouse comparisons. Protein Sci. 2004 13 240-254. 

Pilpel Y, Lancet D. The variable and conserved interfaces of modelled olfactory receptor proteins. Protein Sci. 2002 8 969-977. 

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

Gerber, Stocker, Tanimura and Thum use Drosophila to elucidate the generation of behavior from olfactory and gustatory sensation. The functional anatomy of Drosophila olfactory receptor neurons is described both for mature flies and larvae, which emerge as simpler model system with fewer olfactory receptors and with attraction and repulsion as easily testable, behavioral outcomes. 

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