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Structural Basis of Activation of Bitter Taste Receptor T2R1 and Comparison with Class A G-protein-coupled Receptors (GPCRs) *

Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 286, Issue: 41, Page: 36032-36041
2011
  • 72
    Citations
  • 0
    Usage
  • 82
    Captures
  • 2
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    72
  • Captures
    82
  • Mentions
    2
    • News Mentions
      1
      • News
        1
    • References
      1
      • Wikipedia
        1

Most Recent News

Molecular Cloning and Expression of Taste Receptor Gene T2R1 of Obscure Puffer, Takifugu fasciatus

ABSTRACT Obscure puffer, Takifugu fasciatus is a unique species of China which is distributed in the estuary of the Yangtze River, and belongs to the

Article Description

The human bitter taste receptors (T2Rs) are non-Class A members of the G-protein-coupled receptor (GPCR) superfamily, with very limited structural information. Amino acid sequence analysis reveals that most of the important motifs present in the transmembrane helices (TM1–TM7) of the well studied Class A GPCRs are absent in T2Rs, raising fundamental questions regarding the mechanisms of activation and how T2Rs recognize bitter ligands with diverse chemical structures. In this study, the bitter receptor T2R1 was used to systematically investigate the role of 15 transmembrane amino acids in T2Rs, including 13 highly conserved residues, by amino acid replacements guided by molecular modeling. Functional analysis of the mutants by calcium imaging analysis revealed that replacement of Asn-66 2.65 and the highly conserved Asn-24 1.50 resulted in greater than 90% loss of agonist-induced signaling. Our results show that Asn-24 1.50 plays a crucial role in receptor activation by mediating an hydrogen bond network connecting TM1-TM2-TM7, whereas Asn-66 2.65 is essential for binding to the agonist dextromethorphan. The interhelical hydrogen bond between Asn-24 1.50 and Arg-55 2.54 restrains T2R receptor activity because loss of this bond in I27A and R55A mutants results in hyperactive receptor. The conserved amino acids Leu-197 5.50, Ser-200 5.53, and Leu-201 5.54 form a putative L XX SL motif which performs predominantly a structural role by stabilizing the helical conformation of TM5 at the cytoplasmic end. This study provides for the first time mechanistic insights into the roles of the conserved transmembrane residues in T2Rs and allows comparison of the activation mechanisms of T2Rs with the Class A GPCRs.

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