Is the olfactory receptor a metalloprotein?

The sense of smell is arguably our most primal faculty and also the least understood. Even our own olfactorily impaired species is capable of detecting ≈10,000 distinct scents [Buck, L. & Axel, R. (1991) Cell 65, 175–187]. To achieve that amazing diversity, mammals have ≈1,000 olfactory genes, which accounts for ≈3% of their entire genome [Mombaerts, P. (1999) Science 286, 707–711]. The olfactory receptors (ORs) are believed to be seven-helix transmembrane proteins, with an odorant-binding site on the periplasmic domain and a G protein-binding site on the cytoplasmic domain. Odorants first bind to an OR, which then undergoes some structural change that triggers the G protein activation and the following cascade of events leading to nerve cell activity. The structural details of ORs, however, remain to be determined. In this paper, we will describe a hypothesis in which metal ions play an important role for odorant recognition. We analyze the predicted structure and consensus sequence of the ORs and propose a metal-binding site in the loop between fourth and fifth helix (4–5 loop). We have prepared synthetically a pentapeptide that contains this putative binding site and find that it not only has high affinity for binding Cu(II) and Zn(II) ions, but that it also undergoes a dramatic transition to an α-helical structure upon metal ion binding. Based on these observations, we propose a “shuttlecock” mechanism for the possible structural change in ORs upon odorant binding. This mechanism involves membrane penetration of the 4–5 loop after residue charge neutralization by metal ion binding.