8EX7

Human S1P transporter Spns2 in an outward-facing partially occluded conformation (state 3)

8EX7 の概要

• エントリーDOI: 10.2210/pdb8ex7/pdb
• EMDBエントリー: 28653
• 分子名称: Sphingosine-1-phosphate transporter SPNS2 (1 entity in total)
• 機能のキーワード: transporter, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 48896.18

構造登録者

Ahmed, S.,Zhao, H.,Dai, Y.,Lee, C.H. (登録日: 2022-10-24, 公開日: 2023-05-31, 最終更新日: 2024-06-19)

主引用文献

Chen, H.,Ahmed, S.,Zhao, H.,Elghobashi-Meinhardt, N.,Dai, Y.,Kim, J.H.,McDonald, J.G.,Li, X.,Lee, C.H.
Structural and functional insights into Spns2-mediated transport of sphingosine-1-phosphate.
Cell, 186:2644-, 2023

PubMed Abstract: Sphingosine-1-phosphate (S1P) is an important signaling sphingolipid that regulates the immune system, angiogenesis, auditory function, and epithelial and endothelial barrier integrity. Spinster homolog 2 (Spns2) is an S1P transporter that exports S1P to initiate lipid signaling cascades. Modulating Spns2 activity can be beneficial in treatments of cancer, inflammation, and immune diseases. However, the transport mechanism of Spns2 and its inhibition remain unclear. Here, we present six cryo-EM structures of human Spns2 in lipid nanodiscs, including two functionally relevant intermediate conformations that link the inward- and outward-facing states, to reveal the structural basis of the S1P transport cycle. Functional analyses suggest that Spns2 exports S1P via facilitated diffusion, a mechanism distinct from other MFS lipid transporters. Finally, we show that the Spns2 inhibitor 16d attenuates the transport activity by locking Spns2 in the inward-facing state. Our work sheds light on Spns2-mediated S1P transport and aids the development of advanced Spns2 inhibitors.

PubMed: 37224812
DOI: 10.1016/j.cell.2023.04.028

実験手法

ELECTRON MICROSCOPY (3.53 Å)