Label-free, real-time monitoring of membrane binding events at zeptomolar concentrations using frequency-locked optical microresonators

Gin, Adley; Nguyen, Phuong-Diem; Melzer, Jeffrey E.; Li, Cheng; Strzelinski, Hannah; Liggett, Stephen B.; Su, Judith

doi:10.1038/s41467-024-51320-x

Nat Commun

2024

DOI: 10.1038/s41467-024-51320-x

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Label-free, real-time monitoring of membrane binding events at zeptomolar concentrations using frequency-locked optical microresonators

Adley Gin,

Phuong-Diem Nguyen,

Jeffrey E. Melzer

et al.

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Cited by 3 publications

References 70 publications

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Steviol rebaudiosides bind to four different sites of the human sweet taste receptor (T1R2/T1R3) complex explaining confusing experiments

Hao,

Guthrie,

Kim

et al. 2024

Commun Chem

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Steviol rebaudiosides bind to four different sites of the human sweet taste receptor (T1R2/T1R3) complex explaining confusing experiments

Hao,

Guthrie,

Kim

et al. 2024

Commun Chem

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Agonist activation to open the Gα subunit of the GPCR–G protein precoupled complex defines functional agonist activation of TAS2R5

Young Yang,

Duy Mac,

Strzelinski

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) regulate multiple cellular responses and represent highly successful therapeutic targets. The mechanisms by which agonists activate the G protein are unclear for many GPCR families, including the bitter taste receptors (TAS2Rs). We ascertained TAS2R5 properties by live cell-based functional assays, direct binding affinity measurements using optical resonators, and atomistic molecular dynamics simulations. We focus on three agonists that exhibit a wide range of signal transduction in cells despite comparable ligand–receptor binding energies derived from direct experiment and computation. Metadynamics simulations revealed that the critical barrier to activation is ligand-induced opening of the G protein between the α-helical (AH) and Ras-like domains of Gα subunit from a precoupled TAS2R5-G protein state to the fully activated state. A moderate agonist opens the AH-Ras cleft from 22 Å to 31 Å with an energy gain of −4.8 kcal mol −1 , making GDP water-exposed for signaling. A high-potency agonist had an energy gain of −11.1 kcal mol −1 . The low-potency agonist is also exothermic for Gα opening, but with an energy gain of only −1.4 kcal mol −1 . This demonstrates that TAS2R5 agonist-bound functional potencies are derived from energy gains in the transition from a precoupled complex at the level of Gα opening. Our experimental and computational study provides insights into the activation mechanism of signal transduction that provide a basis for rational design of new drugs.

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Whispering gallery mode optical resonators for biological and chemical detection: current practices, future perspectives, and challenges

Hao,

2024

Rep. Prog. Phys.

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Sensors are important for a wide variety of applications include medical diagnostics and environmental monitoring. Due to their long photon confinement times, whispering gallery mode sensors are among the most sensitive sensors currently in existence. We briefly discuss what are whispering gallery mode sensors, the principles of whispering gallery mode sensing, and the history of the field, beginning with Mie theory. We discuss recent work in the field on using these whispering gallery mode resonators as sensors, focusing particularly on biological and chemical sensing applications. We discuss how sensorgrams are acquired and fundamental measurement limits. In addition, we discuss how to interpret binding curves and extract physical parameters such as binding affinity constants. We discuss the controversy surrounding single-molecule detection and discuss hybrid whispering gallery mode nanoparticle sensors. In addition, we place these sensors in context with others sensing technologies both labeled and label-free. Finally, we discuss what we believe are the most promising applications for these devices, outline remaining challenges, and provide an outlook for the future.

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Label-free, real-time monitoring of membrane binding events at zeptomolar concentrations using frequency-locked optical microresonators

Cited by 3 publications

References 70 publications

Steviol rebaudiosides bind to four different sites of the human sweet taste receptor (T1R2/T1R3) complex explaining confusing experiments

Steviol rebaudiosides bind to four different sites of the human sweet taste receptor (T1R2/T1R3) complex explaining confusing experiments

Agonist activation to open the Gα subunit of the GPCR–G protein precoupled complex defines functional agonist activation of TAS2R5

Whispering gallery mode optical resonators for biological and chemical detection: current practices, future perspectives, and challenges

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