Positive/Negative Allosteric Modulation Switching in an Umami Taste Receptor (T1R1/T1R3) by a Natural Flavor Compound, Methional

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Author(s)

    • 中北 智哉 Toda Yasuka
    • Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo・Department of Agricultural Chemistry, Faculty of Agriculture, Meiji University
    • Nakagita Tomoya
    • Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo・Department of Cell Biology, Graduate School of Medicine, Kyoto University
    • Hirokawa Takatsugu
    • Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST)
    • Narukawa Masataka
    • Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
    • Ishimaru Yoshiro
    • Department of Agricultural Chemistry, Faculty of Agriculture, Meiji University
    • Misaka Takumi
    • Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo

Abstract

Taste is a vital sensation for vertebrates, enabling the detection of nutritionally important substances or potential toxins. A heteromeric complex of two class C GPCRs, T1R1 and T1R3, was identified as the umami (savory) taste receptor. Amino acids and 5′-ribonucleotides are well known to be natural ligands for human T1R1/T1R3. In this study, we reveal that methional, which is a familiar flavor component in foods, is an allosteric modulator of T1R1/T1R3. Receptor expression experiments showed that methional served as a positive allosteric modulator (PAM) of human T1R1/T1R3 and functioned as a negative allosteric modulator (NAM) of mouse T1R1/T1R3. Although amino acids and 5′-ribonucleotides bound to the extracellular domain of T1R1, the use of interspecies chimeric receptors demonstrated that methional interacted with the transmembrane domain of T1R1. Site-directed mutagenesis and molecular modeling showed that methional could potentially bind at two distinct sites in the transmembrane domain of T1R1 and that the amino acid residues in the bottom of the allosteric pocket engendered the switch between the PAM and NAM modes, which could contribute to switching the binding position of methional. These results may be applicable for elucidating the molecular mechanisms underlying ligand recognition by other class C GPCRs.

Journal

  • Scientific Reports

    Scientific Reports (8), 2018-08-07

    Springer Nature America, Inc

Codes

  • NII Article ID (NAID)
    120006546000
  • Text Lang
    ENG
  • Article Type
    journal article
  • ISSN
    2045-2322
  • Data Source
    IR 
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