Aldehyde Recognition and Discrimination by Mammalian Odorant Receptors via Functional Group-Specific Hydration Chemistry

Abstract

The mammalian odorant receptors (ORs) form a chemical-detecting interface between the atmosphere and the nervous system. This large gene family is composed of hundreds of membrane proteins predicted to form as many unique small molecule binding niches within their G-protein coupled receptor (GPCR) framework, but very little is known about the molecular recognition strategies they use to bind and discriminate between small molecule odorants. Using rationally designed synthetic analogs of a typical aliphatic aldehyde, we report evidence that among the ORs showing specificity for the aldehyde functional group, a significant percentage detect the aldehyde through its ability to react with water to form a 1,1-geminal (gem)-diol. Evidence is presented indicating that the rat OR-I7, an often-studied and modeled OR known to require the aldehyde function of octanal for activation, is likely one of the gem-diol activated receptors. A homology model based on an activated GPCR X-ray structure provides a structural hypothesis for activation of OR-I7 by the gem-diol of octanal.

Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by ( R )-muscone and diverse other musk-smelling compounds

“…Note that the binding site for these musksmelling compounds is near the extracellular loop (ECL2, at the periphery) of both receptors ( Fig. 5 A and B), in contrast to the deep binding site proposed for smaller odorants in the ORI7, OR2AG1, MOR244-3, and OR-EG receptors (49,50,(64)(65)(66)(67).…”

Dynamical Binding Modes Determine Agonistic and Antagonistic Ligand Effects in the Prostate-Specific G-Protein Coupled Receptor (PSGR)

“…However, this is a general problem with modelling odorant receptors. The success of generating homology models of ORs based on crystal structures of rhodopsin and other GPCRs (see refs 33 , 38 – 40 , 50 – 52 ) justifies homology modelling of ORs to construct molecular models. However, these models per se have predictive character, but cannot be taken as competitors of experimentally resolved structures.…”

Conformational Sensing by a Mammalian Olfactory Receptor

“…It can be seen in Figure4Ct hat the octanal and 3-cis response averages reachedap lateau between3and 10 mm,c onsistent at least in the octanal case with that ligand's I7 EC 50 of about 1 mm. [8,31] Unexpectedly, 3-trans had reached its maximum response by 3 mm,p ossibly indicating al ower EC 50 ,b ut because we did not test lower concentrations we could not estimate the EC 50 value. Strikingly, the 3-trans efficacy was 33 % higher than octanal's at 3 mm (p value < 0.00002, Welch's ttest), indicating it is as ignificantlym ore efficacious agonist than octanal, which is generally considered to be af ull I7 agonist.…”

“…Since our goal was to compare the efficacy produced by octanal and its two conformational mimics in each cell,w el imited this analysis to the OSNs that showedar esponse to all three aldehydes. Since the EC 50 of octanal is about2mm, [8,31] cells that did not respond to octanal by 10 mm (4 cells) were omitted from this analysis resultingi natotal of 120 cells. The cell-by-cell responses of these cells are shown in heatmapf ormat relative to the forskolin response in Figure S4.…”