title: Exchanging ligand-binding specificity between a pair of mouse olfactory receptor paralogs reveals odorant recognition principles.
abstract: A multi-gene family of ~1000 G protein-coupled olfactory receptors (ORs) constitutes the molecular basis of mammalian olfaction. Due to the lack of structural data its remarkable capacity to detect and discriminate thousands of odorants remains poorly understood on the structural level of the receptor. Using site-directed mutagenesis we transferred ligand specificity between two functionally related ORs and thereby revealed amino acid residues of central importance for odorant recognition and discrimination of the two receptors. By exchanging two of three residues, differing at equivalent positions of the putative odorant binding site between the mouse OR paralogs Olfr73 (mOR-EG) and Olfr74 (mOR-EV), we selectively changed ligand preference but remarkably also signaling activation strength in both ORs. Computer modeling proposed structural details at atomic resolution how the very same odorant molecule might interact with different contact residues to induce different functional responses in two related receptors. Our findings provide a mechanistic explanation of how the olfactory system distinguishes different molecular aspects of a given odorant molecule, and unravel important molecular details of the combinatorial encoding of odorant identity at the OR level.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne Switzerland.
authors.forename: Olivia
authors.initials: O
authors.lastname: Baud
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne Switzerland.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne Switzerland.
authors.forename: Luc
authors.initials: L
authors.lastname: Veya
authors.affiliation: Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne Switzerland.
authors.forename: Horst
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne Switzerland.
authors.forename: Horst
authors.initials: H
authors.lastname: Pick
mesh_terms: D000080462:Acyclic Monoterpenes; D000818:Animals; D001547:Benzaldehydes / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D002460:Cell Line; D003517:Cyclopentanes / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009812:Odorants; D009930:Organic Chemicals / Q000737:chemistry / Q000378:metabolism*; D054883:Oxylipins / Q000737:chemistry / Q000378:metabolism; D000081223:Polycyclic Sesquiterpenes; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018035:Receptors, Odorant / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism; D012903:Smell
chemical_list: D000080462:Acyclic Monoterpenes; D001547:Benzaldehydes; D003517:Cyclopentanes; D008024:Ligands; D008840:Microfilament Proteins; D039821:Monoterpenes; D009930:Organic Chemicals; D054883:Oxylipins; D000081223:Polycyclic Sesquiterpenes; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D018035:Receptors, Odorant; D012717:Sesquiterpenes; C544141:Olfr73 protein, mouse; C581370:rose-oxide; C050302:nootkatone; C086299:jasmone; C045941:ethyl vanillin