Issue 38, 2025

Structural basis of the residence time of adenosine A2A receptor ligands revealed by NMR

Abstract

Residence time, which refers to the average duration a drug remains bound to its receptor, is a crucial parameter in determining its pharmacological effects. However, the mechanisms governing the residence time of G protein-coupled receptor (GPCR) ligands remain unclear. In this study, we observed NMR signals from the methyl groups of alanine and methionine located at the intersection of the binding cavity and extracellular loops of A2AAR under conditions where E165Q and T256A mutations led to reduced residence times. Our NMR analysis revealed that the spatial arrangement surrounding the E165–H264 salt bridge correlates with residence time. These findings provide quantitative insights into residence time and could assist in the development of drugs with optimized effects.

Graphical abstract: Structural basis of the residence time of adenosine A2A receptor ligands revealed by NMR

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Article information

Article type
Edge Article
Submitted
30 Mar 2025
Accepted
27 Aug 2025
First published
29 Aug 2025
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2025,16, 17948-17955

Structural basis of the residence time of adenosine A2A receptor ligands revealed by NMR

T. Ueda, T. Tsuchida, M. Kurita, T. Mizumura, S. Imai, Y. Shiraishi, Y. Kofuku, S. Miyakawa, K. Fukuzawa, K. Takeuchi and I. Shimada, Chem. Sci., 2025, 16, 17948 DOI: 10.1039/D5SC02398J

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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