8VY9

CryoEM structure of Ggust-coupled TAS2R14 with cholesterol and an intracellular tastant

This is a non-PDB format compatible entry.

Summary for 8VY9

• Entry DOI: 10.2210/pdb8vy9/pdb
• Related: 8VY7
• EMDB information: 43647 43650 43656
• Descriptor: Guanine nucleotide-binding protein G(t) subunit alpha-3, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: gpcr, complex, signaling protein, taste receptor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 193366.32

Authors

Kim, Y.,Gumpper, R.H.,Roth, B.L. (deposition date: 2024-02-07, release date: 2024-04-03, Last modification date: 2024-11-13)

Primary citation

Kim, Y.,Gumpper, R.H.,Liu, Y.,Kocak, D.D.,Xiong, Y.,Cao, C.,Deng, Z.,Krumm, B.E.,Jain, M.K.,Zhang, S.,Jin, J.,Roth, B.L.
Bitter taste receptor activation by cholesterol and an intracellular tastant.
Nature, 628:664-671, 2024

PubMed Abstract: Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with G (also known as gustducin) and G. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of G and G. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.

PubMed: 38600377
DOI: 10.1038/s41586-024-07253-y

Experimental method

ELECTRON MICROSCOPY (2.88 Å)