Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect
ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors

View Author Information
Institute of Chemistry - Nice, UMR 7272 CNRS - University Nice - Sophia Antipolis, 06108 Nice cedex 2, France
Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States
§ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, United States
Cite this: J. Am. Chem. Soc. 2015, 137, 26, 8611–8616
Publication Date (Web):June 19, 2015
https://doi.org/10.1021/jacs.5b04659
Copyright © 2015 American Chemical Society

    Article Views

    2100

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (3)»

    Abstract

    Abstract Image

    Odorant receptor (OR) genes and proteins represent more than 2% of our genome and 4% of our proteome and constitute the largest subgroup of G protein-coupled receptors (GPCRs). The mechanism underlying OR activation remains poorly understood, as they do not share some of the highly conserved motifs critical for activation of non-olfactory GPCRs. By combining site-directed mutagenesis, heterologous expression, and molecular dynamics simulations that capture the conformational change of constitutively active mutants, we tentatively identified crucial residues for the function of these receptors using the mouse MOR256-3 (Olfr124) as a model. The toggle switch for sensing agonists involves a highly conserved tyrosine residue in helix VI. The ionic lock is located between the “DRY” motif in helix III and a positively charged “R/K” residue in helix VI. This study provides an unprecedented model that captures the main mechanisms of odorant receptor activation.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    Alignment of GPCR sequences, full dose–response curves, supplementary figures and structures of the OR models. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.5b04659.

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 55 publications.

    1. Lorenza Pirona, Federico Ballabio, Mercedes Alfonso-Prieto, Riccardo Capelli. Calcium-Driven In Silico Inactivation of a Human Olfactory Receptor. Journal of Chemical Information and Modeling 2024, 64 (8) , 2971-2978. https://doi.org/10.1021/acs.jcim.4c00249
    2. Juan Wang, Danqing Wang, Mingquan Huang, Baoguo Sun, Fazheng Ren, Jihong Wu, Jinglin Zhang, Hehe Li, Xiaotao Sun. Decoding Molecular Mechanism Underlying Human Olfactory Receptor OR8D1 Activation by Sotolone Enantiomers. Journal of Agricultural and Food Chemistry 2024, 72 (10) , 5403-5415. https://doi.org/10.1021/acs.jafc.3c09142
    3. Mercedes Alfonso-Prieto, Riccardo Capelli. Machine Learning-Based Modeling of Olfactory Receptors in Their Inactive State: Human OR51E2 as a Case Study. Journal of Chemical Information and Modeling 2023, 63 (10) , 2911-2917. https://doi.org/10.1021/acs.jcim.3c00380
    4. Alessandro Nicoli, Franziska Haag, Patrick Marcinek, Ruiming He, Johanna Kreißl, Jörg Stein, Alessandro Marchetto, Andreas Dunkel, Thomas Hofmann, Dietmar Krautwurst, Antonella Di Pizio. Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1. Journal of Chemical Information and Modeling 2023, 63 (7) , 2014-2029. https://doi.org/10.1021/acs.jcim.2c00752
    5. Mengfan He, Weihong Liu, Chen Zhang, Yingjian Liu, Hanyi Zhuang, David O’Hagan. Selectively Fluorinated Citronellol Analogues Support a Hydrogen Bonding Donor Interaction with the Human OR1A1 Olfactory Receptor. Organic Letters 2022, 24 (24) , 4415-4420. https://doi.org/10.1021/acs.orglett.2c01635
    6. Xiaojing Cong, Wenwen Ren, Jody Pacalon, Rui Xu, Lun Xu, Xuewen Li, Claire A. de March, Hiroaki Matsunami, Hongmeng Yu, Yiqun Yu, Jérôme Golebiowski. Large-Scale G Protein-Coupled Olfactory Receptor–Ligand Pairing. ACS Central Science 2022, 8 (3) , 379-387. https://doi.org/10.1021/acscentsci.1c01495
    7. Mihwa Na, Min Ting Liu, Minh Q. Nguyen, Kevin Ryan. Single-Neuron Comparison of the Olfactory Receptor Response to Deuterated and Nondeuterated Odorants. ACS Chemical Neuroscience 2019, 10 (1) , 552-562. https://doi.org/10.1021/acschemneuro.8b00416
    8. Eric Block. Molecular Basis of Mammalian Odor Discrimination: A Status Report. Journal of Agricultural and Food Chemistry 2018, 66 (51) , 13346-13366. https://doi.org/10.1021/acs.jafc.8b04471
    9. Xiaojing Cong, Sébastien Fiorucci, Jérôme Golebiowski. Activation Dynamics of the Neurotensin G Protein-Coupled Receptor 1. Journal of Chemical Theory and Computation 2018, 14 (8) , 4467-4473. https://doi.org/10.1021/acs.jctc.8b00216
    10. C. Bushdid, C. A. de March, S. Fiorucci, H. Matsunami, J. Golebiowski. Agonists of G-Protein-Coupled Odorant Receptors Are Predicted from Chemical Features. The Journal of Physical Chemistry Letters 2018, 9 (9) , 2235-2240. https://doi.org/10.1021/acs.jpclett.8b00633
    11. Seogjoo Jang and Changbong Hyeon . Kinetic Model for the Activation of Mammalian Olfactory Receptor. The Journal of Physical Chemistry B 2017, 121 (6) , 1304-1311. https://doi.org/10.1021/acs.jpcb.7b00486
    12. Chenyang Wu, Marc Xu, Junlin Dong, Wenqiang Cui, Shuguang Yuan. The structure and function of olfactory receptors. Trends in Pharmacological Sciences 2024, 45 (3) , 268-280. https://doi.org/10.1016/j.tips.2024.01.004
    13. Li Xu, Hong-Bo Jiang, Jie-Ling Yu, Deng Pan, Yong Tao, Quan Lei, Yang Chen, Zhao Liu, Jin-Jun Wang. Two odorant receptors regulate 1-octen-3-ol induced oviposition behavior in the oriental fruit fly. Communications Biology 2023, 6 (1) https://doi.org/10.1038/s42003-023-04551-5
    14. Yosuke Fukutani, Masashi Abe, Haruka Saito, Ryo Eguchi, Toshiaki Tazawa, Claire A. de March, Masafumi Yohda, Hiroaki Matsunami. Antagonistic interactions between odorants alter human odor perception. Current Biology 2023, 33 (11) , 2235-2245.e4. https://doi.org/10.1016/j.cub.2023.04.072
    15. Christian B. Billesbølle, Claire A. de March, Wijnand J. C. van der Velden, Ning Ma, Jeevan Tewari, Claudia Llinas del Torrent, Linus Li, Bryan Faust, Nagarajan Vaidehi, Hiroaki Matsunami, Aashish Manglik. Structural basis of odorant recognition by a human odorant receptor. Nature 2023, 615 (7953) , 742-749. https://doi.org/10.1038/s41586-023-05798-y
    16. Troy W. Lowry, Aubrey E. Kusi-Appiah, Debra Ann Fadool, Steven Lenhert. Odor Discrimination by Lipid Membranes. Membranes 2023, 13 (2) , 151. https://doi.org/10.3390/membranes13020151
    17. Claire A. de March, Hiroaki Matsunami, Masashi Abe, Matthew Cobb, Kara C. Hoover. Genetic and functional odorant receptor variation in the Homo lineage. iScience 2023, 26 (1) , 105908. https://doi.org/10.1016/j.isci.2022.105908
    18. Anna Lagunas, Christine Belloir, Loïc Briand, Pau Gorostiza, Josep Samitier. Determination of the nanoscale electrical properties of olfactory receptor hOR1A1 and their dependence on ligand binding: Towards the development of capacitance-operated odorant biosensors. Biosensors and Bioelectronics 2022, 218 , 114755. https://doi.org/10.1016/j.bios.2022.114755
    19. Tammy Shim, Jody Pacalon, Won-Cheol Kim, Xiaojing Cong, Jérémie Topin, Jérôme Golebiowski, Cheil Moon. The Third Extracellular Loop of Mammalian Odorant Receptors Is Involved in Ligand Binding. International Journal of Molecular Sciences 2022, 23 (20) , 12501. https://doi.org/10.3390/ijms232012501
    20. Yiqun Yu, Zhenjie Ma, Jody Pacalon, Lun Xu, Weihao Li, Christine Belloir, Jeremie Topin, Loïc Briand, Jérôme Golebiowski, Xiaojing Cong. Extracellular loop 2 of G protein–coupled olfactory receptors is critical for odorant recognition. Journal of Biological Chemistry 2022, 298 (9) , 102331. https://doi.org/10.1016/j.jbc.2022.102331
    21. Rui Xu, Xiaojing Cong, Qian Zheng, Lun Xu, Mengjue J. Ni, Claire A. de March, Hiroaki Matsunami, Jérôme Golebiowski, Minghong Ma, Yiqun Yu. Interactions among key residues regulate mammalian odorant receptor trafficking. The FASEB Journal 2022, 36 (7) https://doi.org/10.1096/fj.202200116RR
    22. Jérémie Topin, Cédric Bouysset, Jody Pacalon, Yiseul Kim, Mee-Ra Rhyu, Sébastien Fiorucci, Jérôme Golebiowski. Functional molecular switches of mammalian G protein-coupled bitter-taste receptors. Cellular and Molecular Life Sciences 2021, 78 (23) , 7605-7615. https://doi.org/10.1007/s00018-021-03968-7
    23. Amara Jabeen, Claire A. de March, Hiroaki Matsunami, Shoba Ranganathan. Machine Learning Assisted Approach for Finding Novel High Activity Agonists of Human Ectopic Olfactory Receptors. International Journal of Molecular Sciences 2021, 22 (21) , 11546. https://doi.org/10.3390/ijms222111546
    24. Maura Malinska, Soo-Kyung Kim, William Goddard, Manasa Ashok. Structural Variation and Odorant Binding for Olfactory Receptors Selected from the Six Major Subclasses of the OR Phylogenetic Tree. 2021, 855-925. https://doi.org/10.1007/978-3-030-18778-1_37
    25. Min Ting Liu, Mihwa Na, Yadi Li, Mark R. Biscoe, Kevin Ryan. Conformational Sensing by a Mammalian Olfactory Receptor. Chemistry – A European Journal 2020, 26 (50) , 11462-11469. https://doi.org/10.1002/chem.202001390
    26. NaHye Lee, YoonGyu Jae, Minhyung Kim, TaeHo Cho, ChaeEun Lee, Yu Ri Hong, Do Young Hyeon, Sanghyun Ahn, Hongmok Kwon, Kyul Kim, Jae Hoon Jung, Sehyun Chae, Jeong‐Oh Shin, Jinwoong Bok, Youngjoo Byun, Daehee Hwang, JaeHyung Koo. A pathogen‐derived metabolite induces microglial activation via odorant receptors. The FEBS Journal 2020, 287 (17) , 3841-3870. https://doi.org/10.1111/febs.15234
    27. Franziska Haag, Lucky Ahmed, Krystle Reiss, Eric Block, Victor S. Batista, Dietmar Krautwurst. Copper-mediated thiol potentiation and mutagenesis-guided modeling suggest a highly conserved copper-binding motif in human OR2M3. Cellular and Molecular Life Sciences 2020, 77 (11) , 2157-2179. https://doi.org/10.1007/s00018-019-03279-y
    28. Zhe Zhang, Xiang Gao, Qinghua Zhang, Weming Li. Constitutive activity of a spermine receptor is maintained by a single site in the C-terminal. Biochemical and Biophysical Research Communications 2020, 526 (2) , 389-395. https://doi.org/10.1016/j.bbrc.2020.03.053
    29. Xiaoyang Serene Hu, Kentaro Ikegami, Aashutosh Vihani, Kevin W. Zhu, Marcelo Zapata, Claire A. de March, Matthew Do, Natasha Vaidya, Gary Kucera, Cheryl Bock, Yue Jiang, Masafumi Yohda, Hiroaki Matsunami. Concentration-Dependent Recruitment of Mammalian Odorant Receptors. eneuro 2020, 7 (2) , ENEURO.0103-19.2019. https://doi.org/10.1523/ENEURO.0103-19.2019
    30. Amara Jabeen, Ramya Vijayram, Shoba Ranganathan. A two-stage computational approach to predict novel ligands for a chemosensory receptor. Current Research in Structural Biology 2020, 2 , 213-221. https://doi.org/10.1016/j.crstbi.2020.10.001
    31. Manon Genva, Tierry Kenne Kemene, Magali Deleu, Laurence Lins, Marie-Laure Fauconnier. Is It Possible to Predict the Odor of a Molecule on the Basis of its Structure?. International Journal of Molecular Sciences 2019, 20 (12) , 3018. https://doi.org/10.3390/ijms20123018
    32. Xiaojing Cong, Qian Zheng, Wenwen Ren, Jean-Baptiste Chéron, Sébastien Fiorucci, Tieqiao Wen, Chunbo Zhang, Hongmeng Yu, Jérôme Golebiowski, Yiqun Yu. Zebrafish olfactory receptors ORAs differentially detect bile acids and bile salts. Journal of Biological Chemistry 2019, 294 (17) , 6762-6771. https://doi.org/10.1074/jbc.RA118.006483
    33. L. Verzeaux, S. Richer, J. Viguier, S. Gofflo, D. Boudier, E. Aymard, B. Closs. Structure‐function relationship between a natural cosmetic active ingredient and the olfactory receptor OR2AT4. International Journal of Cosmetic Science 2019, 41 (2) , 194-199. https://doi.org/10.1111/ics.12526
    34. Caroline Bushdid, Claire A. de March, Jérémie Topin, Matthew Do, Hiroaki Matsunami, Jérôme Golebiowski. Mammalian class I odorant receptors exhibit a conserved vestibular-binding pocket. Cellular and Molecular Life Sciences 2019, 76 (5) , 995-1004. https://doi.org/10.1007/s00018-018-2996-4
    35. Amara Jabeen, Abidali Mohamedali, Shoba Ranganathan. Looking for Missing Proteins. 2019https://doi.org/10.1016/B978-0-12-809633-8.20167-2
    36. Liyun Zhang, Yuan Yuan, Tian Ren, Yanzhi Guo, Chuan Li, Xuemei Pu. Shining Light on Molecular Mechanism for Odor-selectivity of CNT-immobilized Olfactory Receptor. Scientific Reports 2018, 8 (1) https://doi.org/10.1038/s41598-018-26105-0
    37. Ji Hyun Bak, Seogjoo J. Jang, Changbong Hyeon, . Implications for human odor sensing revealed from the statistics of odorant-receptor interactions. PLOS Computational Biology 2018, 14 (5) , e1006175. https://doi.org/10.1371/journal.pcbi.1006175
    38. Claire A. de March, Jérémie Topin, Elise Bruguera, Gleb Novikov, Kentaro Ikegami, Hiroaki Matsunami, Jérôme Golebiowski. Odorant Receptor 7D4 Activation Dynamics. Angewandte Chemie 2018, 130 (17) , 4644-4648. https://doi.org/10.1002/ange.201713065
    39. Claire A. de March, Jérémie Topin, Elise Bruguera, Gleb Novikov, Kentaro Ikegami, Hiroaki Matsunami, Jérôme Golebiowski. Odorant Receptor 7D4 Activation Dynamics. Angewandte Chemie International Edition 2018, 57 (17) , 4554-4558. https://doi.org/10.1002/anie.201713065
    40. Maik Behrens, Loïc Briand, Claire A de March, Hiroaki Matsunami, Atsuko Yamashita, Wolfgang Meyerhof, Simone Weyand. Structure–Function Relationships of Olfactory and Taste Receptors. Chemical Senses 2018, 43 (2) , 81-87. https://doi.org/10.1093/chemse/bjx083
    41. Caroline Bushdid, Claire A. de March, Hiroaki Matsunami, Jérôme Golebiowski. Numerical Models and In Vitro Assays to Study Odorant Receptors. 2018, 77-93. https://doi.org/10.1007/978-1-4939-8609-5_7
    42. Xiaojing Cong, Jérôme Golebiowski. Allosteric Na + -binding site modulates CXCR4 activation. Physical Chemistry Chemical Physics 2018, 20 (38) , 24915-24920. https://doi.org/10.1039/C8CP04134B
    43. Min Ting Liu, Jianghai Ho, Jason Karl Liu, Radhanath Purakait, Uriel N. Morzan, Lucky Ahmed, Victor S. Batista, Hiroaki Matsunami, Kevin Ryan. Carbon chain shape selectivity by the mouse olfactory receptor OR-I7. Organic & Biomolecular Chemistry 2018, 16 (14) , 2541-2548. https://doi.org/10.1039/C8OB00205C
    44. Francesco Raimondi, Matthew J. Betts, Qianhao Lu, Asuka Inoue, J. Silvio Gutkind, Robert B. Russell. Genetic variants affecting equivalent protein family positions reflect human diversity. Scientific Reports 2017, 7 (1) https://doi.org/10.1038/s41598-017-12971-7
    45. Steffen Wolf, Nikolina Jovancevic, Lian Gelis, Sebastian Pietsch, Hanns Hatt, Klaus Gerwert. Dynamical Binding Modes Determine Agonistic and Antagonistic Ligand Effects in the Prostate-Specific G-Protein Coupled Receptor (PSGR). Scientific Reports 2017, 7 (1) https://doi.org/10.1038/s41598-017-16001-4
    46. Christiane Geithe, Jonas Protze, Franziska Kreuchwig, Gerd Krause, Dietmar Krautwurst. Structural determinants of a conserved enantiomer-selective carvone binding pocket in the human odorant receptor OR1A1. Cellular and Molecular Life Sciences 2017, 74 (22) , 4209-4229. https://doi.org/10.1007/s00018-017-2576-z
    47. Fabrizio Fierro, Eda Suku, Mercedes Alfonso-Prieto, Alejandro Giorgetti, Sven Cichon, Paolo Carloni. Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis. Frontiers in Molecular Biosciences 2017, 4 https://doi.org/10.3389/fmolb.2017.00063
    48. Bernie Byunghoon Park, NaHye Lee, YunHye Kim, YoonGyu Jae, Seunghyun Choi, NaNa Kang, Yu Ri Hong, Kiwon Ok, Jeonghee Cho, Young Ho Jeon, Eun Hee Lee, Youngjoo Byun, JaeHyung Koo. Analogues of Dehydroacetic Acid as Selective and Potent Agonists of an Ectopic Odorant Receptor through a Combination of Hydrophilic and Hydrophobic Interactions. ChemMedChem 2017, 12 (7) , 477-482. https://doi.org/10.1002/cmdc.201600612
    49. Jean-Baptiste Chéron, Jérôme Golebiowski, Serge Antonczak, Sébastien Fiorucci. The anatomy of mammalian sweet taste receptors. Proteins: Structure, Function, and Bioinformatics 2017, 85 (2) , 332-341. https://doi.org/10.1002/prot.25228
    50. Erich H. Schneider, Roland Seifert. Pharmacological Characterization of Human Histamine Receptors and Histamine Receptor Mutants in the Sf9 Cell Expression System. 2017, 63-118. https://doi.org/10.1007/164_2016_124
    51. Christine Belloir, Marie-Louise Miller-Leseigneur, Fabrice Neiers, Loïc Briand, Anne-Marie Le Bon. Biophysical and functional characterization of the human olfactory receptor OR1A1 expressed in a mammalian inducible cell line. Protein Expression and Purification 2017, 129 , 31-43. https://doi.org/10.1016/j.pep.2016.09.006
    52. Blythe D. Shepard, Lydie Cheval, Zita Peterlin, Stuart Firestein, Hermann Koepsell, Alain Doucet, Jennifer L. Pluznick. A Renal Olfactory Receptor Aids in Kidney Glucose Handling. Scientific Reports 2016, 6 (1) https://doi.org/10.1038/srep35215
    53. Anna Reese, Nanna Holmgaard List, Jacob Kongsted, Ilia A. Solov’yov, . How Far Does a Receptor Influence Vibrational Properties of an Odorant?. PLOS ONE 2016, 11 (3) , e0152345. https://doi.org/10.1371/journal.pone.0152345
    54. Bassim Tazir, Mona Khan, Peter Mombaerts, Xavier Grosmaitre, . The extremely broad odorant response profile of mouse olfactory sensory neurons expressing the odorant receptor MOR256‐17 includes trace amine‐associated receptor ligands. European Journal of Neuroscience 2016, 43 (5) , 608-617. https://doi.org/10.1111/ejn.13153
    55. Yiqun Yu, Claire A. de March, Mengjue J. Ni, Kaylin A. Adipietro, Jérôme Golebiowski, Hiroaki Matsunami, Minghong Ma. Responsiveness of G protein-coupled odorant receptors is partially attributed to the activation mechanism. Proceedings of the National Academy of Sciences 2015, 112 (48) , 14966-14971. https://doi.org/10.1073/pnas.1517510112