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Published September 30, 2021 | Accepted Version + Supplemental Material
Journal Article Open

Structures and Agonist Binding Sites of Bitter Taste Receptor TAS2R5 Complexed with Gi Protein and Validated against Experiment

Abstract

Bitter taste receptors (TAS2Rs) function in taste perception, but are also expressed in many extraoral tissues, presenting attractive therapeutic targets. TAS2R5s expressed on human airway smooth muscle cells can induce bronchodilation for treating asthma and other obstructive diseases. But TAS2R5s display low agonist affinity and the lack of a 3D structure has hindered efforts to design more active ligands. We report the structure of the activated TAS2R5 coupled to the Gi protein and bound to each of 19 agonists, using computational approaches. These agonists bind to two polar residues in TM3 that are unique for TAS2R5 among 25 TAS2R subtypes. Our predicted results correlate well with experimental results of agonist-receptor signaling coefficients, providing validation of the predicted structure. These results provide highly specific data on how agonists activate TAS2R5, how modifications of ligand structure alter receptor activation, and a guide to structure-based drug design.

Additional Information

© 2021 American Chemical Society. Received 4 July 2021. Accepted 31 August 2021. Published online 20 September 2021. Published in issue 30 September 2021. This research was supported by grants from the NIH (1R01HL155532 and P01HL114471). We thank Dr. Amirhossein Mafi for helpful discussions. The computational resource for this research was provided by KISTI National Supercomputing Center (KSC-2018-CHA-0049). The authors declare no competing financial interest.

Attached Files

Accepted Version - nihms-1758358.pdf

Supplemental Material - jz1c02162_si_001.pdf

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Additional details

Created:
August 20, 2023
Modified:
October 23, 2023