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 approximately 10,000 distinct scents Buck, L. & Axel, R. (1991) Cell 65, 175-187. To achieve that amazing diversity, mammals have approximately 1,000 olfactory genes, which accounts for approximately 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 alpha-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.