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Molecular mechanisms underlying differential odor responses of a mouse olfactory receptor

Floriano, Wely B. and Vaidehi, Nagarajan and Goddard, William A., III and Singer, Michael S. and Shepherd, Gordon M. (2000) Molecular mechanisms underlying differential odor responses of a mouse olfactory receptor. Proceedings of the National Academy of Sciences of the United States of America, 97 (20). pp. 10712-10716. ISSN 0027-8424. PMCID PMC27088. doi:10.1073/pnas.97.20.10712.

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The prevailing paradigm for G protein-coupled receptors is that each receptor is narrowly tuned to its ligand and closely related agonists. An outstanding problem is whether this paradigm applies to olfactory receptor (ORs), which is the largest gene family in the genome, in which each of 1,000 different G protein-coupled receptors is believed to interact with a range of different odor molecules from the many thousands that comprise “odor space.” Insights into how these interactions occur are essential for understanding the sense of smell. Key questions are: (i) Is there a binding pocket? (ii) Which amino acid residues in the binding pocket contribute to peak affinities? (iii) How do affinities change with changes in agonist structure? To approach these questions, we have combined single-cell PCR results [Malnic, B., Hirono, J., Sato, T. & Buck, L. B. (1999) Cell 96, 713–723] and well-established molecular dynamics methods to model the structure of a specific OR (OR S25) and its interactions with 24 odor compounds. This receptor structure not only points to a likely odor-binding site but also independently predicts the two compounds that experimentally best activate OR S25. The results provide a mechanistic model for olfactory transduction at the molecular level and show how the basic G protein-coupled receptor template is adapted for encoding the enormous odor space. This combined approach can significantly enhance the identification of ligands for the many members of the OR family and also may shed light on other protein families that exhibit broad specificities, such as chemokine receptors and P450 oxidases.

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Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2000 National Academy of Sciences. Contributed by William A. Goddard III, July 14, 2000. We thank the Army Research Office (Multidisciplinary University Research Initiative, Dr. Robert Campbell) for support of this collaborative effort. The facilities of the Materials and Process Simulation Center used in this project are supported also by the Department of Energy (ASCI ASAP), National Science Foundation (CHE and MRI), Army Research Office, Chevron Corp., MMM, Beckman Institute, Seiko-Epson, Exxon, Dow Chemical, Avery-Dennison Corp., National Aeronautics and Space Administration, National Institutes of Health HD (W.A.G.), Asahi Chemical, and BP Chemical. This work is also supported by National Institute on Deafness and Other Communication Disorders (G.M.S.); National Institute on Aging, National Aeronautics and Space Administration, and National Institute of Mental Health (Human Brain Project, G.M.S.); Yale Medical Scientist Training Program (M.S.S.); and National Institute of Mental Health (IAIMS, M.S.S.).
Funding AgencyGrant Number
Army Research Office (ARO)UNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
Chevron CorporationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Dow Chemical CompanyUNSPECIFIED
National Institute on Deafness and Other Communication DisordersUNSPECIFIED
National Institute on AgingUNSPECIFIED
National Institute of Mental Health (NIMH)UNSPECIFIED
Yale UniversityUNSPECIFIED
Issue or Number:20
PubMed Central ID:PMC27088
Record Number:CaltechAUTHORS:20141121-143114886
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Official Citation:Wely B. Floriano, Nagarajan Vaidehi, William A. Goddard III, Michael S. Singer, and Gordon M. Shepherd Molecular mechanisms underlying differential odor responses of a mouse olfactory receptor PNAS 2000 97 (20) 10712-10716; doi:10.1073/pnas.97.20.10712
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:52056
Deposited By: Tony Diaz
Deposited On:21 Nov 2014 23:20
Last Modified:10 Nov 2021 19:20

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