9ZLW

Human Mfsd2b bound to S1P in outward-facing conformation, digitonin extraction

Summary for 9ZLW

• Entry DOI: 10.2210/pdb9zlw/pdb
• EMDB information: 74414
• Descriptor: Sphingosine-1-phosphate transporter MFSD2B, (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate (2 entities in total)
• Functional Keywords: transporter, lipid, outward facing, substrate bound, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 47968.28

Authors

Ahmed, S.,Dai, Y.,Lee, C.H. (deposition date: 2025-12-09, release date: 2026-10-21)

Primary citation

Ahmed, S.,Huang, M.,Dai, Y.,Yang, X.,Dong, J.,Yu, X.,Lee, C.H.,Nguyen, L.N.
Structure and mechanism of human sphingosine-1-phosphate transporter MFSD2B.
Nat Commun, 17:-, 2026

PubMed Abstract: Sphingosine-1-phosphate (S1P) is an essential signaling lipid that maintains vascular integrity and regulates immune cell trafficking. The major facilitator superfamily domain-containing protein 2B (MFSD2B) serves as the main S1P exporter in red blood cells and platelets; however, its structure and transport mechanism are unclear. Here, we report the 3.0 Å cryo-EM structure of human MFSD2B bound to S1P. S1P is captured in a distinctive binding state, deeply buried within the C-domain, with its sphingoid tail accommodated by a hydrophobic pocket and its phosphate group coordinated by a cluster of polar residues within the transporter's cavity. Mutagenesis and molecular dynamics simulations identify the TM2/TM11 lateral opening as the primary pathway for S1P translocation, with key charged residues acting as sequential anchors during transport. Furthermore, we demonstrate that MFSD2B functions as a uniporter, and that subtle rewiring of local charge networks can alter its coupling mechanism. Our work provides a molecular framework for understanding S1P transport mediated by MFSD2B in hematopoietic cells.

PubMed: 42717192
DOI: 10.1038/s41467-026-76690-2

Experimental method

ELECTRON MICROSCOPY (3.08 Å)