2. Academic Validation
  3. Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case

Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case

  • Sci Rep. 2017 Aug 15;7(1):8223. doi: 10.1038/s41598-017-08344-9.
Antonella Di Pizio 1,  Louisa-Marie Kruetzfeldt 2,  Shira Cheled-Shoval 3 4,  Wolfgang Meyerhof 2,  Maik Behrens 2,  Masha Y Niv 5
Affiliations

Affiliations

  • 1 The Institute of Biochemistry, Food and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, 76100 Rehovot, and The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem, 91904, Israel. adipizio@mail.huji.ac.il.
  • 2 German Institute of Human Nutrition Potsdam-Rehbruecke, Dept. Molecular Genetics, 14558, Nuthetal, Germany.
  • 3 The Institute of Biochemistry, Food and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, 76100 Rehovot, and The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem, 91904, Israel.
  • 4 Department of Animal Science, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, 76100, Israel.
  • 5 The Institute of Biochemistry, Food and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, 76100 Rehovot, and The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem, 91904, Israel. masha.niv@mail.huji.ac.il.
PMID: 28811548 DOI: 10.1038/s41598-017-08344-9
Abstract

Bitter taste is one of the basic taste modalities, warning against consuming potential poisons. Bitter compounds activate members of the bitter Taste Receptor (Tas2r) subfamily of G protein-coupled receptors (GPCRs). The number of functional Tas2rs is species-dependent. Chickens represent an intriguing minimalistic model, because they detect the bitter taste of structurally different molecules with merely three bitter Taste Receptor subtypes. We investigated the binding modes of several known agonists of a representative chicken bitter Taste Receptor, ggTas2r1. Because of low sequence similarity between ggTas2r1 and crystallized GPCRs (~10% identity, ~30% similarity at most), the combination of computational approaches with site-directed mutagenesis was used to characterize the agonist-bound conformation of ggTas2r1 binding site between TMs 3, 5, 6 and 7. We found that the ligand interactions with N93 in TM3 and/or N247 in TM5, combined with hydrophobic contacts, are typically involved in agonist recognition. Next, the ggTas2r1 structural model was successfully used to identify three quinine analogues (epiquinidine, ethylhydrocupreine, quinidine) as new ggTas2r1 agonists. The integrated approach validated here may be applicable to additional cases where the sequence identity of the GPCR of interest and the existing experimental structures is low.

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