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- PDB-8j2f: Human neutral shpingomyelinase -

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Basic information

Entry
Database: PDB / ID: 8j2f
TitleHuman neutral shpingomyelinase
ComponentsSphingomyelin phosphodiesterase 2
KeywordsMEMBRANE PROTEIN / enzyme
Function / homology
Function and homology information


sphingomyelin metabolic process / Glycosphingolipid metabolism / sphingomyelin catabolic process / Ceramide signalling / sphingomyelin phosphodiesterase / sphingomyelin phosphodiesterase activity / sphingolipid catabolic process / ceramide biosynthetic process / TNFR1-mediated ceramide production / phosphoric diester hydrolase activity ...sphingomyelin metabolic process / Glycosphingolipid metabolism / sphingomyelin catabolic process / Ceramide signalling / sphingomyelin phosphodiesterase / sphingomyelin phosphodiesterase activity / sphingolipid catabolic process / ceramide biosynthetic process / TNFR1-mediated ceramide production / phosphoric diester hydrolase activity / caveola / cell periphery / 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
TETRADECANE / HEPTANE / Sphingomyelin phosphodiesterase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsZhang, S.S.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation / citation_author
Item: _citation.page_last / _citation.pdbx_database_id_PubMed ..._citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sphingomyelin phosphodiesterase 2
B: Sphingomyelin phosphodiesterase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,0518
Polymers95,4052
Non-polymers6466
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sphingomyelin phosphodiesterase 2 / / Lyso-platelet-activating factor-phospholipase C / Lyso-PAF-PLC / Neutral sphingomyelinase / N-SMase ...Lyso-platelet-activating factor-phospholipase C / Lyso-PAF-PLC / Neutral sphingomyelinase / N-SMase / nSMase / nSMase1


Mass: 47702.508 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMPD2 / Production host: Homo sapiens (human)
References: UniProt: O60906, sphingomyelin phosphodiesterase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-HP6 / HEPTANE / Heptane


Mass: 100.202 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H16
#4: Chemical ChemComp-C14 / TETRADECANE / Tetradecane


Mass: 198.388 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H30
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human neutral sphingomyelinases / Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 220000 / Symmetry type: POINT

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