Structural basis of the residence time of adenosine A <sub>2A</sub> receptor ligands revealed by NMR

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 A<sub>2A</sub>AR 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.

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Publication Details

Journal
Chemical Science
Published
2025-01-01
DOI
https://doi.org/10.1039/d5sc02398j
Citations
2
Primary Topic
Adenosine and Purinergic Signaling
Type
article
Field-Weighted Citation Impact
2.24

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article

Structural basis of the residence time of adenosine A 2A receptor ligands revealed by NMR

Takuya Mizumura, Koh Takeuchi, Ichio Shimada, Tomoki Tsuchida et al.
2 citations
Chemical Science
Adenosine and Purinergic Signaling
2.24
article

Structural basis of the residence time of adenosine A 2A receptor ligands revealed by NMR

Takuya Mizumura, Koh Takeuchi, Ichio Shimada, Tomoki Tsuchida, Shunsuke Imai, Yutaka Kofuku, Kaori Fukuzawa, Takumi Ueda, Yutaro Shiraishi, Masanori Kurita, Shuhei Miyakawa
article en
2 citations

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 A<sub>2A</sub>AR 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.

Chemical ScienceVol. 16(38)
Hiroshima University (JP), RIKEN Center for Integrative Medical Sciences (JP), The University of Tokyo (JP), The University of Osaka (JP)
Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Japan Society for the Promotion of Science, RIKEN, RIKEN Center for Biosystems Dynamics Research
Openalex Percentile: Top 12%
Adenosine and Purinergic Signaling
2.24
DOIOpen Access PDFOpenAlex
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Structural basis of the residence time of adenosine A <sub>2A</sub> receptor ligands revealed by NMR — Takuya Mizumura, Koh Takeuchi, et al. · Chemical Science (2025) | TGRS Research Map | TGRS