Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes
Abstract
The 25 human bitter taste receptors (TAS2Rs) are expressed on taste and extra-oral cells representing an integrated chemosensory system. The archetypal TAS2R14 is activated by > 150 topographically diverse agonists, raising the question of how this uncharacteristic accommodation is achieved for these GPCRs. We report the computationally derived structure of TAS2R14 with binding sites and energies for five highly diverse agonists. Remarkably, the binding pocket is the same for all five agonists. The energies derived from molecular dynamics are consistent with experiments determining signal transduction coefficients in live cells. TAS2R14 accommodates agonists through the breaking of a TMD3 H-bond instead of the prototypic strong salt bridge, a TMD1,2,7 interaction different from Class A GPCRs, and agonist-promoted TMD3 salt bridges for high affinity (which we confirmed by receptor mutagenesis). Thus, the broadly tuned TAS2Rs accommodate diverse agonists via a single (vs multiple) binding pocket through unique TM interactions for sensing disparate micro-environments.
Additional Information
© 2023 California Institute of California. Under a Creative Commons license - Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) We thank Moon Young Yang for helpful suggestions, Lauren Lujan for technical assistance, and Himeshkumar N. Patel and Katherine Vargas for assistance in article preparation. This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) grants HL155532 and HL11447 and by The Cargill Food Company. Author contributions. A.T. and D.K. contributed equally to this work. A.T. performed the structure predictions, modeling, and simulations; D.K. performed the cell-based experiments; S-KK, S.B.L., and W.A.G. designed the experiments and computations; B.G. and all other authors contributed to the interpretation of results and writing of the article. Data and code availability: 1) All data reported in this paper will be shared by the lead contacts upon request. All structural data is deposited in the indicated repository in the key resources table. 2) No original code is reported in this paper. 3) Any additional information required to reanalyze the data reported in this paper is available from the lead contacts upon request. The authors declare no competing interests.Attached Files
Published - main.pdf
Supplemental Material - 1-s2.0-S2589004223004996-mmc1.pdf
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Additional details
- PMCID
- PMC10121769
- Eprint ID
- 121458
- Resolver ID
- CaltechAUTHORS:20230519-1707000.18
- HL155532
- NIH
- HL114471
- NIH
- Cargill Food Company
- Created
-
2023-05-22Created from EPrint's datestamp field
- Updated
-
2023-06-08Created from EPrint's last_modified field
- Other Numbering System Name
- WAG
- Other Numbering System Identifier
- 1564