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, III,
Stephen B. Liggett
Affiliations
Alina Tokmakova
Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA
Donghwa Kim
Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
Brian Guthrie
Cargill Global Food Research Center, Wayzata, MN 55391, USA
Soo-Kyung Kim
Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA
William A. Goddard, III
Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA; Corresponding author
Stephen B. Liggett
Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA; Corresponding author
Summary: 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.
