Identification and structural characterization of stereochemical promiscuity in a taste receptor.

Authors

Rakuto Mizoguchi, Yasuka Toda, Mana Nagae, Takashi Yoshida, Hiroaki Matsuura, Kunio Hirata, Vi Toan Lam, Duy Phuoc Tran, Akio Kitao, Yohei Miyanoiri, Maiko Hosotani, Yuji Ashikawa, Chiaki Ito, Naotaka Tsutsumi, Norihisa Yasui, Yoshiro Ishimaru, Atsuko Yamashita

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 38. Pages e2534924123. Sep 22, 2026. Epub Sep 15, 2026.

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.

PMID:
42743286
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.

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