Structures and Agonist Binding Sites of Bitter Taste Receptor TAS2R5 Complexed with Gi Protein and Validated against Experiment
- 20 September 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in The Journal of Physical Chemistry Letters
- Vol. 12 (38), 9293-9300
- https://doi.org/10.1021/acs.jpclett.1c02162
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.Funding Information
- KISTI National Supercomputing Center (KSC-2018-CHA-0049)
- NIH (1R01HL155532, P01HL114471)
This publication has 43 references indexed in Scilit:
- Computationally‐predicted CB1 cannabinoid receptor mutants show distinct patterns of salt‐bridges that correlate with their level of constitutive activity reflected in G protein coupling levels, thermal stability, and ligand bindingProteins: Structure, Function, and Bioinformatics, 2013
- Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptorProceedings of the National Academy of Sciences of the United States of America, 2012
- A Simple Method for Quantifying Functional Selectivity and Agonist BiasACS Chemical Neuroscience, 2012
- Bihelix: Towards de novo structure prediction of an ensemble of G‐protein coupled receptor conformationsProteins: Structure, Function, and Bioinformatics, 2011
- Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstructionNature Medicine, 2010
- Predicted 3D structures for adenosine receptors bound to ligands: Comparison to the crystal structureJournal of Structural Biology, 2010
- Bitter Taste Receptors Influence Glucose HomeostasisPLOS ONE, 2008
- Association of Gene Variants With Incident Myocardial Infarction in the Cardiovascular Health StudyArteriosclerosis, Thrombosis, and Vascular Biology, 2008
- Mechanism of the receptor-catalyzed activation of heterotrimeric G proteinsNature Structural & Molecular Biology, 2006
- Receptor and βγ Binding Sites in the α Subunit of the Retinal G Protein TransducinScience, 1997