ACHEMS 2019
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SPLTRAK Abstract Submission
Conformational Sensing by the Mouse Olfactory Receptor Olfr2
Kevin Ryan & Min Ting Liu
Department of Chemistry and Biochemistry, The City College of New York , New York, NY, United States

There is currently no structural biology information describing what takes place inside a mammalian olfactory receptor (OR) when it binds to, and is activated by, an odorant. Especially mysterious is how an odorant’s carbon chain can define the receptive range of an OR. As a model system to investigate carbon chain recognition by ORs, we are studying the rodent Olfr2 receptor (a.k.a. OR-I7), which is specific for the aldehyde group and prefers 8-carbon aliphatic chains. Proteins that bind specifically to small molecules with rotatable bonds typically bind their ligands in one or very few ligand conformations. Carbon chains like that found in octanal can adopt many conformational isomers, or conformers, of similar energy, raising the question: Are specific conformers responsible for OR activation? To investigate this question, we used the medicinal chemistry strategy of conformational restriction. We made and tested in dissociated olfactory receptor neurons from the UbI7 mouse two octanal analogs, cis- and trans-2-(4-ethylcyclohexyl)ethanal. These ligands spatially restrict, in relation to the aldehyde group, in different ways, the last two carbons in the octanal chain. The order of potency of the three ligands was found to be: trans > octanal > cis, and the cis isomer appears to be a partial agonist. Our results support the idea that Olfr2 senses the conformations of the octanal carbon chain. From the data presented we deduce the optimal octanal conformation for Olfr2 activation.