7T6B

Structure of S1PR2-heterotrimeric G13 signaling complex

Summary for 7T6B

• Entry DOI: 10.2210/pdb7t6b/pdb
• EMDB information: 25712
• Descriptor: Guanine nucleotide-binding protein subunit alpha-13, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: s1p, s1pr2, gpcr, membrane protein, cryo-em, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 158154.27

Authors

Li, X.,Chen, H. (deposition date: 2021-12-13, release date: 2022-04-06, Last modification date: 2024-11-20)

Primary citation

Chen, H.,Chen, K.,Huang, W.,Staudt, L.M.,Cyster, J.G.,Li, X.
Structure of S1PR2-heterotrimeric G 13 signaling complex.
Sci Adv, 8:eabn0067-eabn0067, 2022

PubMed Abstract: Sphingosine-1-phosphate (S1P) regulates immune cell trafficking, angiogenesis, and vascular function via its five receptors. Inherited mutations in S1P receptor 2 (S1PR2) occur in individuals with hearing loss, and acquired mutations in S1PR2 and G occur in a malignant lymphoma. Here, we present the cryo-electron microscopy structure of S1P-bound S1PR2 coupled to the heterotrimeric G. Interaction between S1PR2 intracellular loop 2 (ICL2) and transmembrane helix 4 confines ICL2 to engage the α5 helix of G. Transforming growth factor-α shedding assays and cell migration assays support the key roles of the residues in S1PR2-G complex assembly. The structure illuminates the mechanism of receptor disruption by disease-associated mutations. Unexpectedly, we showed that FTY720-P, an agonist of the other four S1PRs, can trigger G activation via S1PR2. S1PR2 variant can increase the activity of G considerably with FTY720-P and S1P, thus revealing a basis for S1PR drug selectivity.

PubMed: 35353559
DOI: 10.1126/sciadv.abn0067

Experimental method

ELECTRON MICROSCOPY (3.19 Å)