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- EMDB-28650: Human S1P transporter Spns2 in an inward-facing open conformation... -
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Open data
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Basic information
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Title | Human S1P transporter Spns2 in an inward-facing open conformation (state 1) | |||||||||
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![]() | transporter / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() regulation of eye pigmentation / regulation of humoral immune response / regulation of T cell migration / sphingolipid transporter activity / lymphocyte migration / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / sphingosine-1-phosphate receptor signaling pathway / lipid transport / T cell homeostasis ...regulation of eye pigmentation / regulation of humoral immune response / regulation of T cell migration / sphingolipid transporter activity / lymphocyte migration / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / sphingosine-1-phosphate receptor signaling pathway / lipid transport / T cell homeostasis / B cell homeostasis / transmembrane transporter activity / lymph node development / sensory perception of sound / bone development / endosome membrane / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.93 Å | |||||||||
![]() | Ahmed S / Zhao H / Dai Y / Lee CH | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural and functional insights into Spns2-mediated transport of sphingosine-1-phosphate. Authors: Hongwen Chen / Shahbaz Ahmed / Hongtu Zhao / Nadia Elghobashi-Meinhardt / Yaxin Dai / Jae Hun Kim / Jeffrey G McDonald / Xiaochun Li / Chia-Hsueh Lee / ![]() ![]() 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 ...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. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 203.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13.7 KB 13.7 KB | Display Display | ![]() |
Images | ![]() | 60.4 KB | ||
Filedesc metadata | ![]() | 5.3 KB | ||
Others | ![]() ![]() | 200.7 MB 200.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8ex4MC ![]() 8ex5C ![]() 8ex6C ![]() 8ex7C ![]() 8ex8C ![]() 8g92C M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.649 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_28650_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
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Density Histograms |
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Sample components
-Entire : Human S1P transporter Spns2 in an inward-facing open conformation...
Entire | Name: Human S1P transporter Spns2 in an inward-facing open conformation (state 1) |
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Components |
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-Supramolecule #1: Human S1P transporter Spns2 in an inward-facing open conformation...
Supramolecule | Name: Human S1P transporter Spns2 in an inward-facing open conformation (state 1) type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Sphingosine-1-phosphate transporter SPNS2
Macromolecule | Name: Sphingosine-1-phosphate transporter SPNS2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 48.896184 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: EKRKAAAAIL SLGNVLNYLD RYTVAGVLLD IQQHFGVKDR GAGLLQSVFI CSFMVAAPIF GYLGDRFNRK VILSCGIFFW SAVTFSSSF IPQQYFWLLV LSRGLVGIGE ASYSTIAPTI IGDLFTKNTR TLMLSVFYFA IPLGSGLGYI TGSSVKQAAG D WHWALRVS ...String: EKRKAAAAIL SLGNVLNYLD RYTVAGVLLD IQQHFGVKDR GAGLLQSVFI CSFMVAAPIF GYLGDRFNRK VILSCGIFFW SAVTFSSSF IPQQYFWLLV LSRGLVGIGE ASYSTIAPTI IGDLFTKNTR TLMLSVFYFA IPLGSGLGYI TGSSVKQAAG D WHWALRVS PVLGMITGTL ILILVPATKR GHADQLGDQL KARTSWLRDM KALIRNRSYV FSSLATSAVS FATGALGMWI PL YLHRAQV VQKTAETCNS PPCGAKDSLI FGAITCFTGF LGVVTGAGAT RWCRLKTQRA DPLVCAVGML GSAIFICLIF VAA KSSIVG AYICIFVGET LLFSNWAITA DILMYVVIPT RRATAVALQS FTSHLLGDAG SPYLIGFISD LIRQSTKDSP LWEF LSLGY ALMLCPFVVV LGGMFFLATA LFFVSDRARA EQQVNQLAMP PASVKV UniProtKB: Sphingosine-1-phosphate transporter SPNS2 |
-Macromolecule #2: (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate
Macromolecule | Name: (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate type: ligand / ID: 2 / Number of copies: 1 / Formula: S1P |
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Molecular weight | Theoretical: 379.472 Da |
Chemical component information | ![]() ChemComp-S1P: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.6 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 842662 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |