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Structure paper

TitleStructural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism.
Journal, issue, pagesNat Chem Biol, Vol. 18, Issue 3, Page 281-288, Year 2022
Publish dateDec 22, 2021
AuthorsZhenmei Xu / Tatsuya Ikuta / Kouki Kawakami / Ryoji Kise / Yu Qian / Ruixue Xia / Ming-Xia Sun / Anqi Zhang / Changyou Guo / Xue-Hui Cai / Zhiwei Huang / Asuka Inoue / Yuanzheng He /
PubMed AbstractSphingosine-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 ...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 β-arrestin. However, a structural basis of biased agonism remains elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of G-bound S1PR1 in complex with S1P, fingolimod-phosphate (FTY720-P) and siponimod (BAF312). In combination with functional assays and molecular dynamics (MD) studies, we reveal that the β-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 and the retained interaction between F265 and N307 are the key features of the β-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.
External linksNat Chem Biol / PubMed:34937912
MethodsEM (single particle)
Resolution2.86 - 3.4 Å
Structure data

31225

7eo2

EMDB-31225, PDB-7eo2:
Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to FTY720p
Method: EM (single particle) / Resolution: 2.89 Å

31226

7eo4

EMDB-31226, PDB-7eo4:
Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to BAF312
Method: EM (single particle) / Resolution: 2.86 Å

32461

7wf7

EMDB-32461, PDB-7wf7:
Cryo-EM of Sphingosine 1-phosphate receptor 1 / Gi complex bound to S1P
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-J89:
(2~{S})-2-azanyl-4-(4-octylphenyl)-2-[[oxidanyl-bis(oxidanylidene)-$l^{6}-phosphanyl]oxymethyl]butan-1-ol

ChemComp-J8C:
1-[[4-[(~{E})-~{N}-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-~{C}-methyl-carbonimidoyl]-2-ethyl-phenyl]methyl]azetidine-3-carboxylic acid / Siponimod

ChemComp-S1P:
(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate / Sphingosine-1-phosphate

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GPCR

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