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- EMDB-29860: Structure of inhibitor 16d-bound SPNS2 -

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Basic information

Entry
Database: EMDB / ID: EMD-29860
TitleStructure of inhibitor 16d-bound SPNS2
Map dataStructure of inhibitor 16d-bound SPNS2
Sample
  • Complex: SPNS2 in complex with inhibitor 16d
    • Protein or peptide: Sphingosine-1-phosphate transporter SPNS2
  • Ligand: 3-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]propan-1-amine
KeywordsSPNS2 / Sphingosine-1-phosphate / major facilitator superfamily / transporter / IMMUNE SYSTEM
Function / homology
Function and homology information


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
Protein spinster-like / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Sphingosine-1-phosphate transporter SPNS2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsChen H / Li X
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM135343 United States
Welch FoundationI-1957 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL160487-01 United States
Damon Runyon Cancer Research FoundationDRR-53S-19 United States
CitationJournal: Cell / Year: 2023
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
DepositionFeb 21, 2023-
Header (metadata) releaseMay 24, 2023-
Map releaseMay 24, 2023-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29860.png

Downloads & links

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Map

FileDownload / File: emd_29860.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of inhibitor 16d-bound SPNS2
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.408
Minimum - Maximum-2.2248669 - 3.3229718
Average (Standard dev.)0.0015938266 (±0.04975885)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 249.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_29860_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_29860_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : SPNS2 in complex with inhibitor 16d

EntireName: SPNS2 in complex with inhibitor 16d
Components
  • Complex: SPNS2 in complex with inhibitor 16d
    • Protein or peptide: Sphingosine-1-phosphate transporter SPNS2
  • Ligand: 3-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]propan-1-amine

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Supramolecule #1: SPNS2 in complex with inhibitor 16d

SupramoleculeName: SPNS2 in complex with inhibitor 16d / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Sphingosine-1-phosphate transporter SPNS2

MacromoleculeName: Sphingosine-1-phosphate transporter SPNS2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.770148 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EKRKAEEEKR KAAAAILSLG NVLNYLDRYT VAGVLLDIQQ HFGVKDRGAG LLQSVFICSF MVAAPIFGYL GDRFNRKVIL SCGIFFWSA VTFSSSFIPQ QYFWLLVLSR GLVGIGEASY STIAPTIIGD LFTKNTRTLM LSVFYFAIPL GSGLGYITGS S VKQAAGDW ...String:
EKRKAEEEKR KAAAAILSLG NVLNYLDRYT VAGVLLDIQQ HFGVKDRGAG LLQSVFICSF MVAAPIFGYL GDRFNRKVIL SCGIFFWSA VTFSSSFIPQ QYFWLLVLSR GLVGIGEASY STIAPTIIGD LFTKNTRTLM LSVFYFAIPL GSGLGYITGS S VKQAAGDW HWALRVSPVL GMITGTLILI LVPATKRGHA DQLGDQLKAR TSWLRDMKAL IRNRSYVFSS LATSAVSFAT GA LGMWIPL YLHRAQVVQK TAETCNSPPC GAKDSLIFGA ITCFTGFLGV VTGAGATRWC RLKTQRADPL VCAVGMLGSA IFI CLIFVA AKSSIVGAYI CIFVGETLLF SNWAITADIL MYVVIPTRRA TAVALQSFTS HLLGDAGSPY LIGFISDLIR QSTK DSPLW EFLSLGYALM LCPFVVVLGG MFFLATALFF VSDRARAEQQ VNQLAMPPAS VKV

UniProtKB: Sphingosine-1-phosphate transporter SPNS2

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Macromolecule #2: 3-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]propan-1-amine

MacromoleculeName: 3-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]propan-1-amine
type: ligand / ID: 2 / Number of copies: 1 / Formula: YUX
Molecular weightTheoretical: 343.506 Da
Chemical component information

ChemComp-YUX:
3-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]propan-1-amine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration10 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 214617
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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