Crystal structure reveals the binding mode and selectivity of a photoswitchable ligand for the adenosine A2A receptor

Tsuyoshi Araya; Yuya Matsuba; Harufumi Suzuki; Tomohiro Doura; Nipawan Nuemket; Eriko Nango; Masaki Yamamoto; Dohyun Im; Hidetsugu Asada; Shigeki Kiyonaka; So Iwata

doi:10.1016/j.bbrc.2023.149393

Crystal structure reveals the binding mode and selectivity of a photoswitchable ligand for the adenosine A_2A receptor

Biochem Biophys Res Commun. 2024 Feb 5:695:149393. doi: 10.1016/j.bbrc.2023.149393. Epub 2023 Dec 20.

Authors

Affiliations

¹ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
² Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, 464-8603, Japan.
³ RIKEN SPring-8 Center, Hyogo, 679-5148, Japan; JASRI, Hyogo, 679-5148, Japan.
⁴ RIKEN SPring-8 Center, Hyogo, 679-5148, Japan; Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Miyagi, 980-8577, Japan.
⁵ RIKEN SPring-8 Center, Hyogo, 679-5148, Japan.
⁶ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan. Electronic address: asada.hidetsugu.4s@kyoto-u.ac.jp.
⁷ Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, 464-8603, Japan; Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Nagoya, 464-8603, Japan. Electronic address: kiyonaka@chembio.nagoya-u.ac.jp.
⁸ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan; RIKEN SPring-8 Center, Hyogo, 679-5148, Japan. Electronic address: iwata.so.2z@kyoto-u.ac.jp.

PMID: 38171234
DOI: 10.1016/j.bbrc.2023.149393

Abstract

Rational synthetic expansion of photoresponsive ligands is important for photopharmacological studies. Adenosine A_2A receptor (A_2AR) is stimulated by adenosine and related in Parkinson's disease and other diseases. Here, we report the crystal structure of the A_2AR in complex with the novel photoresponsive ligand photoNECA (blue) at 3.34 Å resolution. PhotoNECA (blue) was designed for this structural study and the cell-based assay showed a photoresponsive and receptor selective characteristics of photoNECA (blue) for A_2AR. The crystal structure explains the binding mode, photoresponsive mechanism and receptor selectivity of photoNECA (blue). Our study would promote not only the rational design of photoresponsive ligands but also dynamic structural studies of A_2AR.

MeSH terms

Adenosine / metabolism
Fluorescent Dyes / chemistry
Humans
Ligands
Parkinson Disease
Photochemistry / methods
Receptor, Adenosine A2A* / chemistry
Receptor, Adenosine A2A* / metabolism

Substances

Adenosine
Ligands
Receptor, Adenosine A2A
Fluorescent Dyes