Mammals can distinguish among thousands of odorants and the first step in this process is the interaction between odorant ligand and odorant receptor (OR). The mammalian odorant receptors constitute an enormous family of G-protein coupled receptors (GPCRs). Sequence analysis has grouped these receptors into two broad classes, with each class further divided into many subfamilies. Several studies, including our preliminary work, indicate that while the members of an OR subfamily recognize similar chemical structures, they can distinguish among these ligands. This project is directed toward understanding how ORs recognize and distinguish among ligands at the molecular level. We have developed a functional assay for ORs using the Xenopus oocyte expression system and robotic electrophysiology.
In Aim 1, we will screen representative ORs from a broad range of subfamilies to identify new ligand - OR pairings.
In Aim 2, we will then clone and functionally express other members of the particular OR subfamilies. Detailed pharmacological analysis will be conducted to reveal differences in ligand specificity among subfamily members. In our third and fourth specific aims, we will combine computational homology modeling and ligand docking with site-directed mutagenesis and functional analysis to identify the structural basis for differences in ligand specificity among members of mammalian odorant receptor subfamilies.
In Aim 3, the Substituted Cysteine Accessibility Method will provide a rigorous test of our computationally derived OR models.
In Aim 4, conventional mutagenesis and functional analysis, conducted based on sequence analysis of the subfamily members, will identify residues that confer differences in ligand specificity. This project will provide an understanding of ligand recognition by mammalian ORs at the molecular level. In addition to specific information about ligand recognition by ORs, this work will be applicable to GPCRs in general. This is important to human health because many current and potential drug targets are GPCRs. Our studies will provide fundamental information about ligand recognition by this important class of receptors. This information will be useful to future efforts in rational drug design.

Public Health Relevance

Humans and other mammals detect odors using an enormous family of receptors (odorant receptors), which are similar in structure to many receptors that are current and future drug targets. This project examines the molecular basis for the ability of odorant receptors to distinguish among the many thousands of odor molecules. Information derived from this work will be useful in understanding the interaction between therapeutic drugs and their target receptors, and may aid in the design of more effective therapeutic drugs.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Sullivan, Susan L
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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Li, Jingyi; Haddad, Rafi; Santos, Vanessa et al. (2015) Receptive range analysis of a mouse odorant receptor subfamily. J Neurochem 134:47-55
Bavan, Selvan; Sherman, Benjamin; Luetje, Charles W et al. (2014) Discovery of novel ligands for mouse olfactory receptor MOR42-3 using an in silico screening approach and in vitro validation. PLoS One 9:e92064
Li, Jingyi; Haddad, Rafi; Chen, Sisi et al. (2012) A broadly tuned mouse odorant receptor that detects nitrotoluenes. J Neurochem 121:881-90
Nichols, Andrew S; Chen, Sisi; Luetje, Charles W (2011) Subunit contributions to insect olfactory receptor function: channel block and odorant recognition. Chem Senses 36:781-90
Goldsmith, Brett R; Mitala, Joseph J; Josue, Jesusa et al. (2011) Biomimetic chemical sensors using nanoelectronic readout of olfactory receptor proteins. ACS Nano 5:5408-16
Pelletier, Julien; Hughes, David T; Luetje, Charles W et al. (2010) An odorant receptor from the southern house mosquito Culex pipiens quinquefasciatus sensitive to oviposition attractants. PLoS One 5:e10090
Wanner, Kevin W; Nichols, Andrew S; Allen, Jean E et al. (2010) Sex pheromone receptor specificity in the European corn borer moth, Ostrinia nubilalis. PLoS One 5:e8685
Nichols, Andrew S; Luetje, Charles W (2010) Transmembrane segment 3 of Drosophila melanogaster odorant receptor subunit 85b contributes to ligand-receptor interactions. J Biol Chem 285:11854-62
Repicky, Sarah E; Luetje, Charles W (2009) Molecular receptive range variation among mouse odorant receptors for aliphatic carboxylic acids. J Neurochem 109:193-202