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

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(48)

Published: Nov. 20, 2024

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

Language: Английский

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

Reports on Progress in Physics, Journal Year: 2024, Volume and Issue: 88(1), P. 016402 - 016402

Published: Dec. 3, 2024

Abstract 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 (WGM) sensors among the most sensitive currently in existence. We briefly discuss what WGM sensors, principles sensing, history field, beginning with Mie theory. recent work field on using these resonators as focusing particularly biological chemical sensing applications. how sensorgrams acquired fundamental measurement limits. In addition, we interpret binding curves extract physical parameters such affinity constants. controversy surrounding single-molecule detection hybrid nanoparticle sensors. place context others technologies both labeled label-free. Finally, believe promising devices, outline remaining challenges, provide an outlook future.

Language: Английский

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Ferrocene-Decorated Graphene Nanosheets built by Edge-to-Face π-π Interaction for Room Temperature ppb-level NO Sensing

Talanta, Journal Year: 2024, Volume and Issue: 285, P. 127365 - 127365

Published: Dec. 12, 2024

Language: Английский

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Towards Early Diagnosis and Screening of Alzheimer’s Disease Using Frequency Locked Whispering Gallery Mode Microtoroid Biosensors

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 17, 2024

Alzheimer’s disease (AD) is a progressive form of dementia affecting almost 55 million people worldwide. It characterized by the abnormal deposition amyloid plaques and neurofibrillary tangles within brain, leading to pathological cascade neuron degeneration death as well memory loss cognitive decline. Amyloid beta (Aβ) an AD biomarker present in cerebrospinal fluid blood serum correlates with presence tau brain. Measuring levels Aβ can help early diagnosis AD, which key for studying novel drugs delaying symptoms dementia. However, this goal difficult achieve due low biomarkers biofluids. Here we demonstrate first time use FLOWER (frequency locked optical whispering evanescent resonator) quantifying post-mortem (CSF) Aβ42 clinicopathologically classified control, mild impairment (MCI), participants. capable measuring CSF (area under curve, AUC = 0.92) higher diagnostic performance than standard ELISA (AUC 0.82) was also able distinguish between control MCI samples. Our results capability screening samples pathology.

Language: Английский

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Optical Positioning and Linking Using Optical Tweezers for 3D Nanofabrication

Advanced Photonics Congress, Journal Year: 2024, Volume and Issue: 9, P. NoTh1D.1 - NoTh1D.1

Published: Jan. 1, 2024

Optical tweezers can accurately position nanoparticles of a wide range materials in complex geometries. Assembly is automated using computer control. Applications include the fabrication grating arrays for free-space coupling into microtoroidal optical sensors.

Language: Английский

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