Molecular Mechanisms Of The Participation Of Metal Ions In Human Olfactory Perception

Organisms detect volatile chemicals using odorant receptors(ORs).We previously identified a crucial role for copper ions in the activation of the mouse OR MOR244-3 by metal-coordinating ligands.However,it is unknown if other mammalian ORs show metal enhancement effects.By ligand-based screening for ORs with metal effects,here we identify a human thiol receptor OR2T11,specifically responding to tert-butyl mercaptan(TBM)and requiring copper for its robust activation.When screened against a series of alcohols,thiols and metal-coordinating ligands,OR2T11 only responds to two-to three-carbon straight-and branched-chain and four-to five-carbon branched-chain thiols as well as(methylthio)methanethiol(MTMT)and derivatives;alcohols are unreactive.We expanded the response profile of MOR244-3 by evaluating the newly-discovered ligands of OR2T11;interestingly,while MOR244-3 also responds to these monothiols,the addition of copper ion elicited unchanged levels of response to the compounds,indicating a flexibility of copper incorporation in the activation of MOR244-3 and possibly divergent activation mechanisms between MOR244-3 and OR2T11.Silver also enhances the response of OR2T11 to thiols,but surprisingly,OR2T11 also has a dose-dependent activity toward silver alone.Saturation transfer difference(STD)nuclear magnetic resonance(NMR)spectroscopy indicates enhanced binding of OR2T11 to TBM in the presence of copper and silver.Finally,we propose a molecular model of OR2T11 harboring two binding sites to the odorant-metal complex or metal ion,which are conformed by site-directed mutagenesis studies.