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Structural Insights into Bitter Taste Receptor TAS2R14 Activation by Cholesterol and an Intracellular Bitter Tastant


Core Concepts
Cholesterol acts as an orthosteric agonist, while the bitter tastant cmpd28.1 functions as a positive allosteric modulator with direct agonist activity at the bitter taste receptor TAS2R14.
Abstract
The article presents structural and functional insights into the bitter taste receptor TAS2R14, which is known to respond to a wide range of structurally diverse tastants. The key findings are: The study reports two cryo-electron microscopy structures of TAS2R14 complexed with the G-proteins Ggust and Gi1. These structures reveal an orthosteric binding pocket occupied by the endogenous ligand cholesterol, as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1. Computational and biochemical analyses validate the binding of both cholesterol and cmpd28.1 to TAS2R14. Cholesterol is identified as an orthosteric agonist, while cmpd28.1 acts as a positive allosteric modulator with direct agonist activity. The orthosteric pocket and allosteric site are connected via an elongated cavity with a hydrophobic core rich in aromatic residues, suggesting a potential mechanism for ligand recognition and signal transduction. The findings provide insights into the diverse ligand recognition capabilities of bitter taste receptors, and suggest that TAS2R14 may have activities beyond bitter taste perception, potentially involving intracellular allosteric tastants.
Stats
The study reports the use of cryo-electron microscopy to determine the structures of TAS2R14 complexed with the G-proteins Ggust and Gi1.
Quotes
"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 Ggust and Gi1." "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."

Deeper Inquiries

How might the structural insights into TAS2R14 activation be leveraged to develop novel bitter taste modulators or therapeutics targeting this receptor?

The structural insights into TAS2R14 activation provide a detailed understanding of the receptor-ligand interactions, highlighting the orthosteric binding pocket occupied by cholesterol and the intracellular allosteric site bound by bitter tastants like cmpd28.1. This knowledge can be leveraged in drug discovery efforts to design novel bitter taste modulators or therapeutics targeting TAS2R14. By utilizing computational modeling and structure-based drug design, researchers can identify small molecules that interact with either the orthosteric or allosteric sites of TAS2R14 to modulate its activity. These modulators could act as agonists, antagonists, or allosteric modulators, influencing the receptor's signaling pathways and potentially altering bitter taste perception or other physiological responses mediated by TAS2R14.

What other intracellular signaling pathways or physiological processes might be influenced by the activation of TAS2R14 by cholesterol and other allosteric ligands?

Activation of TAS2R14 by cholesterol and other allosteric ligands can potentially influence various intracellular signaling pathways and physiological processes beyond bitter taste perception. TAS2R14 is known to be expressed in extraoral tissues, suggesting its involvement in diverse cellular functions. The receptor's activation by cholesterol and allosteric ligands could impact lipid metabolism, cellular homeostasis, and inflammatory responses. Additionally, TAS2R14 signaling may intersect with pathways related to glucose metabolism, immune modulation, and neurotransmitter release. By modulating TAS2R14 activity, these ligands could have broader effects on cellular signaling cascades, leading to physiological changes in metabolism, inflammation, and sensory perception.

Given the diverse ligand recognition capabilities of TAS2R14, what other endogenous or exogenous compounds might be identified as potential agonists or modulators of this receptor?

The diverse ligand recognition capabilities of TAS2R14 suggest that a wide range of endogenous and exogenous compounds could act as potential agonists or modulators of this receptor. Apart from cholesterol and cmpd28.1, other endogenous compounds like lipids, hormones, and neurotransmitters may interact with TAS2R14 to modulate its activity. Exogenous compounds such as plant-derived phytochemicals, environmental toxins, or pharmaceutical drugs could also serve as ligands for TAS2R14. By screening libraries of natural and synthetic compounds, researchers may identify novel agonists or modulators that target TAS2R14, providing insights into the receptor's role in various physiological processes and potential therapeutic applications.
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