Identification and structural characterization of stereochemical promiscuity in a taste receptor

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Abstract
Taste receptor type 1 (TAS1R), which consists of sweet and umami receptors in humans, senses nutrients (such as sugars and amino acids) with substrate specificity that is often broad and varies among animals and subtypes. However, the structural basis for achieving diverse specificities remains largely elusive. Here, we present the crystal structure of the ligand-binding domain (LBD) of Tas1r1/Tas1r3 heterodimer from pufferfish, an ortholog of the human umami taste receptor. The overall structure of Tas1r1/Tas1r3LBD resembles previously reported TAS1R structures, indicating a conserved core architecture within the family. Nevertheless, pufferfish Tas1r1/Tas1r3 was found to bind and respond to both l - and d -amino acids, even though TAS1Rs are considered to respond to either enantiomer. Structural and mutational analyses revealed that this nonrigorous stereochemical recognition is attributed to intersubdomain interactions that latch the cleft containing the amino acid-binding site. These interactions prevent the cleft from fully opening, thereby stabilizing the active conformation, even if the ligand has a different chirality. These results suggest that different substrate specificities in TAS1Rs can be acquired not only by the gain or loss of direct interactions with the substrate but also by the gain of intramolecular interactions, which alter the conformational equilibrium of the receptor.
Funding Information
  • Japan Society for the Promotion of Science (JP18H04621 JP20H04778 JP20H03195 JP23H02424 JP23K27117 JP24K21272)
  • Japan Society for the Promotion of Science (JP23K26861 JP25H01362)
  • Fusion Oriented REsearch for disruptive Science and Technology (JPMJFR220C)
  • Society for Research on Umami Taste (N/A)
  • Takeda Science Foundation (N/A)
  • Osaka University (N/A)
  • Japan Agency for Medical Research and Development (JP21am0101070 JP23am121001)
  • Lotte Foundation (N/A)
  • Japan Society for the Promotion of Science (JP23H02424 JP24H02259)

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