title: Smelling Sulfur: Copper and Silver Regulate the Response of Human Odorant Receptor OR2T11 to Low-Molecular-Weight Thiols.
abstract: Mammalian survival depends on ultrasensitive olfactory detection of volatile sulfur compounds, since these compounds can signal the presence of rancid food, O2depleted atmospheres, and predators (through carnivore excretions). Skunks exploit this sensitivity with their noxious spray. In commerce, natural and liquefied gases are odorized with t-BuSH and EtSH, respectively, as warnings. The 100-million-fold difference in olfactory perception between structurally similar EtSH and EtOH has long puzzled those studying olfaction. Mammals detect thiols and other odorants using odorant receptors (ORs), members of the family of seven transmembrane G-protein-coupled receptors (GPCRs). Understanding the regulator cofactors and response of ORs is particularly challenging due to the lack of X-ray structural models. Here, we combine computational modeling and site-directed mutagenesis with saturation transfer difference (STD) NMR spectroscopy and measurements of the receptor response profiles. We find that human thiol receptor OR2T11 responds specifically to gas odorants t-BuSH and EtSH requiring ionic copper for its robust activation and that this role of copper is mimicked by ionic and nanoparticulate silver. While copper is both an essential nutrient for life and, in excess, a hallmark of various pathologies and neurodegenerative diseases, its involvement in human olfaction has not been previously demonstrated. When screened against a series of alcohols, thiols, sulfides, and metal-coordinating ligands, OR2T11 responds with enhancement by copper to the mouse semiochemical CH3SCH2SH and derivatives, to four-membered cyclic sulfide thietane and to one- to four-carbon straight- and branched-chain and five-carbon branched-chain thiols but not to longer chain thiols, suggesting compact receptor dimensions. Alcohols are unreactive.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiaotong University School of Medicine , Shanghai 200025, China.
authors.forename: Shengju
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Lucky
authors.initials: L
authors.lastname: Ahmed
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiaotong University School of Medicine , Shanghai 200025, China.
authors.forename: Ruina
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiaotong University School of Medicine , Shanghai 200025, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Molecular Genetics and Microbiology and Department of Neurobiology, Duke Institute for Brain Sciences, Duke University Medical Center , Durham, North Carolina 27710, United States.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsunami
authors.affiliation: Applied Chemicals and Materials Division, National Institute of Standards and Technology , Boulder, Colorado 80305, United States.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Burger
authors.affiliation: Department of Chemistry, University at Albany, State University of New York , Albany, New York 12222, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Block
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Batista
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiaotong University School of Medicine , Shanghai 200025, China.|Institute of Health Sciences, Shanghai Jiaotong University School of Medicine/Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences , Shanghai 200031, China.
authors.forename: Hanyi
authors.initials: H
authors.lastname: Zhuang