Adenosine A2A Receptor (A2AAR) Ligand Screening Using the 19F-NMR Probe FPPA

Zhang, Jinfeng; Feng, Dandan; Cheng, Jianjun; Wüthrich, Kurt

doi:10.1021/jacs.3c04218

Cited by 3 publications

(1 citation statement)

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“…A 2A AR was shown to be the major target for influencing the immunosuppressive effects of adenosine in tumor microenvironments [52,53]. Detailed structural characterization of A 2A AR is an ongoing part of projects aimed at developing new cancer drugs that target this GPCR [54,55].…”

Section: Discussionmentioning

confidence: 99%

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs

et al. 2023

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Eight hundred and twenty-six human G protein-coupled receptors (GPCRs) mediate the actions of two-thirds of the human hormones and neurotransmitters and over one-third of clinically used drugs. Studying the structure and dynamics of human GPCRs in lipid bilayer environments resembling the native cell membrane milieu is of great interest as a basis for understanding structure–function relationships and thus benefits continued drug development. Here, we incorporate the human A2A adenosine receptor (A2AAR) into lipid nanodiscs, which represent a detergent-free environment for structural studies using nuclear magnetic resonance (NMR) in solution. The [15N,1H]-TROSY correlation spectra confirmed that the complex of [u-15N, ~70% 2H]-A2AAR with an inverse agonist adopts its global fold in lipid nanodiscs in solution at physiological temperature. The global assessment led to two observations of practical interest. First, A2AAR in nanodiscs can be stored for at least one month at 4 °C in an aqueous solvent. Second, LMNG/CHS micelles are a very close mimic of the environment of A2AAR in nanodiscs. The NMR signal of five individually assigned tryptophan indole 15N–1H moieties located in different regions of the receptor structure further enabled a detailed assessment of the impact of nanodiscs and LMNG/CHS micelles on the local structure and dynamics of A2AAR. As expected, the largest effects were observed near the lipid–water interface along the intra- and extracellular surfaces, indicating possible roles of tryptophan side chains in stabilizing GPCRs in lipid bilayer membranes.

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Section: Discussionmentioning

confidence: 99%

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs

et al. 2023

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NMR of proteins and nucleic acids

Andrew Atkinson

2024

Nuclear Magnetic Resonance

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Perspectives on Applications of 19F-NMR in Fragment-Based Drug Discovery

Li,

Kang

2024

Molecules

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Fragment-based drug discovery is a powerful approach in drug discovery, applicable to a wide range of targets. This method enables the discovery of potent compounds that can modulate target functions, starting from fragment compounds that bind weakly to the targets. While biochemical, biophysical, and cell-based assays are commonly used to identify fragments, 19F-NMR spectroscopy has emerged as a powerful tool for exploring interactions between biomolecules and ligands. Because fluorine atoms are not naturally present in biological systems, 19F-NMR serves as a sensitive method for fragment screening against diverse targets. Herein, we reviewed the applications of 19F-NMR in fragment screening, highlighting its effectiveness in identifying fragments that bind weakly to various targets such as proteins and RNA. The accumulated evidence suggests that 19F-NMR will continue to be a crucial tool in drug discovery.

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Adenosine A_2A Receptor (A_2AAR) Ligand Screening Using the ¹⁹F-NMR Probe FPPA

Cited by 3 publications

References 30 publications

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs

NMR of proteins and nucleic acids

Perspectives on Applications of 19F-NMR in Fragment-Based Drug Discovery

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