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- EMDB-35948: Human neutral shpingomyelinase -

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Basic information

Entry
Database: EMDB / ID: EMD-35948
TitleHuman neutral shpingomyelinase
Map data
Sample
  • Complex: human neutral sphingomyelinases
    • Protein or peptide: Sphingomyelin phosphodiesterase 2
  • Ligand: MAGNESIUM ION
  • Ligand: HEPTANE
  • Ligand: TETRADECANE
Keywordsenzyme / membrane protein
Function / homology
Function and homology information


sphingomyelin metabolic process / sphingomyelin catabolic process / Ceramide signalling / sphingomyelin phosphodiesterase / sphingomyelin phosphodiesterase activity / sphingolipid catabolic process / ceramide biosynthetic process / Glycosphingolipid catabolism / phosphoric diester hydrolase activity / TNFR1-mediated ceramide production ...sphingomyelin metabolic process / sphingomyelin catabolic process / Ceramide signalling / sphingomyelin phosphodiesterase / sphingomyelin phosphodiesterase activity / sphingolipid catabolic process / ceramide biosynthetic process / Glycosphingolipid catabolism / phosphoric diester hydrolase activity / TNFR1-mediated ceramide production / cell periphery / caveola / endoplasmic reticulum / metal ion binding / plasma membrane
Similarity search - Function
Sphingomyelin phosphodiesterase 2-like / Endonuclease/exonuclease/phosphatase / Endonuclease/Exonuclease/phosphatase family / Endonuclease/exonuclease/phosphatase superfamily
Similarity search - Domain/homology
Sphingomyelin phosphodiesterase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsZhang SS
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32030056 China
CitationJournal: Nat Commun / Year: 2023
Title: Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2).
Authors: Jingbo Yi / Boya Qi / Jian Yin / Ruochong Li / Xudong Chen / Junhan Hu / Guohui Li / Sensen Zhang / Yuebin Zhang / Maojun Yang /
Abstract: Enzymatic breakdown of sphingomyelin by sphingomyelinase (SMase) is the main source of the membrane lipids, ceramides, which are involved in many cellular physiological processes. However, the full- ...Enzymatic breakdown of sphingomyelin by sphingomyelinase (SMase) is the main source of the membrane lipids, ceramides, which are involved in many cellular physiological processes. However, the full-length structure of human neutral SMase has not been resolved; therefore, its catalytic mechanism remains unknown. Here, we resolve the structure of human full-length neutral SMase, sphingomyelinase 1 (SMPD2), which reveals that C-terminal transmembrane helices contribute to dimeric architecture of hSMPD2 and that D111 - K116 loop domain is essential for substrate hydrolysis. Coupled with molecular docking, we clarify the binding pose of sphingomyelin, and site-directed mutagenesis further confirms key residues responsible for sphingomyelin binding. Hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamic (MD) simulations are utilized to elaborate the catalysis of hSMPD2 with the reported in vitro substrates, sphingomyelin and lyso-platelet activating fator (lyso-PAF). Our study provides mechanistic details that enhance our knowledge of lipid metabolism and may lead to an improved understanding of ceramide in disease and in cancer treatment.
History
DepositionApr 14, 2023-
Header (metadata) releaseDec 6, 2023-
Map releaseDec 6, 2023-
UpdateMay 1, 2024-
Current statusMay 1, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_35948.png

Downloads & links

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Map

FileDownload / File: emd_35948.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 224 pix.
= 187.578 Å		0.84 Å/pix.
x 224 pix.
= 187.578 Å		0.84 Å/pix.
x 224 pix.
= 187.578 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8374 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0169
Minimum - Maximum-0.0784279 - 0.12921256
Average (Standard dev.)0.00023703527 (±0.0037429759)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 187.5776 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_35948_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_35948_half_map_2.map
Projections & Slices
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Sample components

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Entire : human neutral sphingomyelinases

EntireName: human neutral sphingomyelinases
Components
  • Complex: human neutral sphingomyelinases
    • Protein or peptide: Sphingomyelin phosphodiesterase 2
  • Ligand: MAGNESIUM ION
  • Ligand: HEPTANE
  • Ligand: TETRADECANE

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Supramolecule #1: human neutral sphingomyelinases

SupramoleculeName: human neutral sphingomyelinases / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sphingomyelin phosphodiesterase 2

MacromoleculeName: Sphingomyelin phosphodiesterase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: sphingomyelin phosphodiesterase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.702508 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKPNFSLRLR IFNLNCWGIP YLSKHRADRM RRLGDFLNQE SFDLALLEEV WSEQDFQYLR QKLSPTYPAA HHFRSGIIGS GLCVFSKHP IQELTQHIYT LNGYPYMIHH GDWFSGKAVG LLVLHLSGMV LNAYVTHLHA EYNRQKDIYL AHRVAQAWEL A QFIHHTSK ...String:
MKPNFSLRLR IFNLNCWGIP YLSKHRADRM RRLGDFLNQE SFDLALLEEV WSEQDFQYLR QKLSPTYPAA HHFRSGIIGS GLCVFSKHP IQELTQHIYT LNGYPYMIHH GDWFSGKAVG LLVLHLSGMV LNAYVTHLHA EYNRQKDIYL AHRVAQAWEL A QFIHHTSK KADVVLLCGD LNMHPEDLGC CLLKEWTGLH DAYLETRDFK GSEEGNTMVP KNCYVSQQEL KPFPFGVRID YV LYKAVSG FYISCKSFET TTGFDPHRGT PLSDHEALMA TLFVRHSPPQ QNPSSTHGPA ERSPLMCVLK EAWTELGLGM AQA RWWATF ASYVIGLGLL LLALLCVLAA GGGAGEAAIL LWTPSVGLVL WAGAFYLFHV QEVNGLYRAQ AELQHVLGRA REAQ DLGPE PQPALLLGQQ EGDRTKEQ

UniProtKB: Sphingomyelin phosphodiesterase 2

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Macromolecule #2: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #3: HEPTANE

MacromoleculeName: HEPTANE / type: ligand / ID: 3 / Number of copies: 2 / Formula: HP6
Molecular weightTheoretical: 100.202 Da
Chemical component information

ChemComp-HP6:
HEPTANE

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Macromolecule #4: TETRADECANE

MacromoleculeName: TETRADECANE / type: ligand / ID: 4 / Number of copies: 2 / Formula: C14
Molecular weightTheoretical: 198.388 Da
Chemical component information

ChemComp-C14:
TETRADECANE

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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

BufferpH: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 220000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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