Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes

Alina Tokmakova; Donghwa Kim; Brian Guthrie; Soo-Kyung Kim; William A Goddard 3rd; Stephen B Liggett

doi:10.1016/j.isci.2023.106422

Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes

iScience. 2023 Mar 16;26(4):106422. doi: 10.1016/j.isci.2023.106422. eCollection 2023 Apr 21.

Authors

Alina Tokmakova¹, Donghwa Kim^{2

3}, Brian Guthrie⁴, Soo-Kyung Kim¹, William A Goddard 3rd¹, Stephen B Liggett^{2

3

5}

Affiliations

¹ Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA.
² Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.
³ Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.
⁴ Cargill Global Food Research Center, Wayzata, MN 55391, USA.
⁵ Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.

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.

Keywords: Biochemistry; Biological sciences; Protein structure aspects; Structural biology.

Grants and funding

R01 HL155532/HL/NHLBI NIH HHS/United States