Prediction of Perception: Probing the hOR17‐4 Olfactory Receptor Model with Silicon Analogues of Bourgeonal and Lilial

Abstract

The award of the Nobel prize to Axel [1a] and Buck [1b] for their pioneering studies on the mechanism of odor perception generated high expectations concerning the prediction of olfactory properties. This was perhaps unjustified, as Buck et al.[2a] also discovered that each odorant triggers a combination of different receptors, that odors consequently correspond to complex activation patterns of glomeruli, and that mixtures can even stimulate cortical neurons that are not stimulated by their individual components.[2b] Thus, it seems almost impossible to predict the olfactory properties of a new odorant that has a different affinity to some estimated 347 different human olfactory receptors.[3] Consequently, the design of new odorants relies heavily on structural similarities to the reference compound rather than on the complementarity to the receptor binding site. [4,5] To what extent, however, can we predict the odor and intensity of a new compound on the basis of an olfactory receptor model?To put our understanding of the odorant-receptor interactions to the test we decided to predict the effect of the substitution of a carbon atom for a silicon atom [6] in the lilyof-the-valley odorants lilial (1 a) and bourgeonal (2 a). This C/Si exchange (sila substitution) would affect their molecular shape only subtly, which according to the latest lily-of-thevalley olfactophore [5] should not affect the main character of the odor, only the thresholds and nuances. Lyral [7a] and lilial (1 a) [7b] were the first two ligands for which odorant-receptor complexes were computed by employing the OR5 receptor of rats (= O1r1469) expressed in the baculovirus-Sf9 cell system. [8] In the human olfactory epithelium, the hOR17-4 receptor (= OR1D2) responds to lilial (1 a) and bourgeonal (2 a). It can also be used for quantitative evaluations as it is also expressed in human sperm cells.[9] Furthermore, the hOR17-40 receptor (= OR3A1) in the human olfactory epithelium responds to lilial (1 a), [10] but still the hOR17-4 receptor seemed ideal for a comparison of the in vivo, in vitro, and in silico data.A homology model of the hOR17-4 receptor, based on the crystal structure of bovine rhodopsin (1U19), was generated with the MOLOC software.[11] The sequence alignment of hOR17-4 to 1U19 was based on the published alignment of OR1E1 to bovine rhodopsin, [12] which has a high homology to hOR17-4. In the resulting model, the ligand binding pocket (LBP) is lined with 21 amino acids of the transmembrane (TM) helices plus two of the extracellular loop EL2, thereby forming an almost closed cavity (see the Supporting Information).As for rhodopsin, it is difficult to imagine how a ligand should enter or leave the LBP. Possibly, the long, doublefolded EL2 chain, which seals the extracellular side, unfolds and opens the entrance to the LBP. It has also been suggested [13] that small lipophilic ligands could enter the LBP sideways between TM5 and TM6 when the phenyl ring of F212 (TM5) and the sidechain of I269 (TM6) move to generate another rotam...

Chemosensory Ca2+ Dynamics Correlate with Diverse Behavioral Phenotypes in Human Sperm

“…To identify specific stimuli for OR4D1 and OR7A5, we used the same experimental strategy that we had successfully employed in the past to match human OR-ligand pairs (17,38,(55)(56)(57)74). Given the poor OR surface expression rate typically observed in heterologous cells (47), careful evaluation of single cell Ca 2ϩ responses is imperative, making this an "ultra-low throughput" assay that is neither applicable to the full repertoire of human ORs 5 nor suitable for large scale ligand screening.…”

Experience influences elemental and configural perception of certain binary odour mixtures in newborn rabbits

“…Here, odorants D and E (as A and C) have very different chemical structures and qualities (for humans); therefore, they could potentially compete for distinct olfactory receptor neurons. Indeed, it is conceivable that ligands of a receptor neuron bearing different structural features could also differ in their odour quality (Doszczak et al, 2007;Sanz et al, 2008). Second, the pre-exposure consisted of a long enrichment of the whole environment (1h during 10days) without any conditioning in rats, in contrast to a 5min-long MP-induced conditioning to a given stimulus occurring for 3days as a maximum in rabbit pups.…”

Odorant–Receptor Interactions and Odor Percept: A Chemical Perspective

“…-Our results will allow refinement of the model [28] of the OR1D2 binding site and hence improve our understanding of its nature. However, we have shown that, in this case at least, there is no simple correlation between activation of a single type of receptor and the ultimate odor percept.…”

“…It is generally accepted that odorant recognition is due to a stereoelectronic fit between the odorant molecule and the trans-membrane helices of the receptor proteins. Models based on this concept have been built [27], and recently such a model was reported for OR1D2 [28]. Up to this point, all published agonists for OR1D2 were aldehydes, and the model includes H-bonding of the aldehyde function using the Hatoms of the NH 2 moiety of N125 (TM3) and the OH of Y261 (TM6).…”