8QV6

Structure of human SPNS2 in DDM

8QV6 の概要

• エントリーDOI: 10.2210/pdb8qv6/pdb
• EMDBエントリー: 18668
• 分子名称: Sphingosine-1-phosphate transporter SPNS2, Nanobody D12, DODECYL-BETA-D-MALTOSIDE (3 entities in total)
• 機能のキーワード: slc transporter, membrane protein, s1p, exporter, lipid transport
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75147.30

構造登録者

Li, H.Z.,Pike, A.C.W.,McKinley, G.,Mukhopadhyay, S.M.M.,Moreau, C.,Scacioc, A.,Abrusci, P.,Borkowska, O.,Chalk, R.,Stefanic, S.,Burgess-Brown, N.,Duerr, K.L.,Sauer, D.B. (登録日: 2023-10-17, 公開日: 2025-02-19)

主引用文献

Li, H.Z.,Pike, A.C.W.,Chang, Y.N.,Prakaash, D.,Gelova, Z.,Stanka, J.,Moreau, C.,Scott, H.C.,Wunder, F.,Wolf, G.,Scacioc, A.,McKinley, G.,Batoulis, H.,Mukhopadhyay, S.,Garofoli, A.,Pinto-Fernandez, A.,Kessler, B.M.,Burgess-Brown, N.A.,Stefanic, S.,Wiedmer, T.,Durr, K.L.,Puetter, V.,Ehrmann, A.,Khalid, S.,Ingles-Prieto, A.,Superti-Furga, G.,Sauer, D.B.
Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2.
Nat Commun, 16:721-721, 2025

PubMed Abstract: Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and thereby is central to the pharmacokinetics of this drug when treating multiple sclerosis. Here, we use a combination of cryo-electron microscopy, immunofluorescence, in vitro binding and in vivo S1P export assays, and molecular dynamics simulations to probe SPNS2's substrate binding and transport. These results reveal the transporter's binding mode to its native substrate S1P, the therapeutic FTY720-P, and the reported SPNS2-targeting inhibitor 33p. Further capturing an inward-facing apo state, our structures illuminate the protein's mechanism for exchange between inward-facing and outward-facing conformations. Finally, using these structural, localization, and S1P transport results, we identify how pathogenic mutations ablate the protein's export activity and thereby lead to hearing loss.

PubMed: 39820269
DOI: 10.1038/s41467-025-55942-7

実験手法

ELECTRON MICROSCOPY (3.68 Å)