期刊
NATURE CHEMICAL BIOLOGY
卷 18, 期 3, 页码 281-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00930-3
关键词
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资金
- Startup Funds of HIT Center for Life Sciences
- National Natural Science Foundation of China [32070048]
- KAKENHI [21H04791, 21H051130, JPJSBP120213501]
- Japan Society for the Promotion of Science (JSPS) [19J11256]
- Japan Agency for Medical Research and Development (AMED) [JP19gm5910013, JP20gm0010004, JP20am0101095]
- JST Moonshot Research and Development Program [JPMJMS2023]
- Japan Science and Technology Agency (JST)
- Daiichi Sankyo Foundation of Life Science
- Takeda Science Foundation
- Ono Medical Research Foundation
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [21H04791, 19J11256] Funding Source: KAKEN
This study reveals that p-arrestin-biased ligands direct a distinct activation path in S1PR1 through extensive interplay between the PIF and the NPxxY motifs, with key features including the intermediate flipping of W269(6.48) and the retained interaction between F265(6.44) and N307(7.49). The structural insights provided in this study offer a rational basis for designing novel signaling-biased S1PR modulators.
Sphingosine-1-phosphate receptor 1 (S1PR1) is a master regulator of lymphocyte egress from the lymph node and an established drug target for multiple sclerosis (MS). Mechanistically, therapeutic S1PR1 modulators activate the receptor yet induce sustained internalization through a potent association with beta-arrestin. However, a structural basis of biased agonism remains elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of G(i)-bound S1PR1 in complex with S1P, fingolimod-phosphate (FTY72O-P) and siponimod (BAF312). In combination with functional assays and molecular dynamics (MD) studies, we reveal that the p-arrestin-biased ligands direct a distinct activation path in S1PR1 through the extensive interplay between the PIF and the NPxxY motifs. Specifically, the intermediate flipping of W269(6.48) and the retained interaction between F265(6.44) and N307(7.49) are the key features of the beta-arrestin bias. We further identify ligand-receptor interactions accounting for the S1PR subtype specificity of BAF312. These structural insights provide a rational basis for designing novel signaling-biased S1PR modulators.
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