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- EMDB-38858: Cryo-EM structure of the apo Lac1-Lip1 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-38858
TitleCryo-EM structure of the apo Lac1-Lip1 complex
Map data
Sample
  • Complex: Lac1-Lip1 complex
    • Protein or peptide: Ceramide synthase LAC1
    • Protein or peptide: Ceramide synthase subunit LIP1
  • Ligand: (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE
KeywordsInhibitor / Complex / Transferase
Function / homology
Function and homology information


very-long-chain ceramide synthase / acyl-CoA ceramide synthase complex / Sphingolipid de novo biosynthesis / sphingosine N-acyltransferase activity / ceramide biosynthetic process / nuclear periphery / nuclear envelope / endoplasmic reticulum membrane / endoplasmic reticulum
Similarity search - Function
TRAM/LAG1/CLN8 homology domain / Sphingosine N-acyltransferase Lag1/Lac1-like / TLC domain / TLC domain profile. / TRAM, LAG1 and CLN8 homology domains.
Similarity search - Domain/homology
Ceramide synthase LAC1 / Ceramide synthase subunit LIP1
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast) / Saccharomyces cerevisiae S288C (yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.19 Å
AuthorsXie T / Zhang Z / Fang Q / Gong X
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Structure / Year: 2024
Title: Mechanism of ceramide synthase inhibition by fumonisin B.
Authors: Zike Zhang / Qi Fang / Tian Xie / Xin Gong /
Abstract: Ceramide synthases (CerSs) play crucial roles in sphingolipid metabolism and have emerged as promising drug targets for metabolic diseases, cancers, and antifungal therapy. However, the therapeutic ...Ceramide synthases (CerSs) play crucial roles in sphingolipid metabolism and have emerged as promising drug targets for metabolic diseases, cancers, and antifungal therapy. However, the therapeutic targeting of CerSs has been hindered by a limited understanding of their inhibition mechanisms by small molecules. Fumonisin B (FB) has been extensively studied as a potent inhibitor of eukaryotic CerSs. In this study, we characterize the inhibition mechanism of FB on yeast CerS (yCerS) and determine the structures of both FB-bound and N-acyl-FB-bound yCerS. Through our structural analysis and the observation of N-acylation of FB by yCerS, we propose a potential ping-pong catalytic mechanism for FB N-acylation by yCerS. Lastly, we demonstrate that FB exhibits lower binding affinity for yCerS compared to the C26- coenzyme A (CoA) substrate, suggesting that the potent inhibitory effect of FB on yCerS may primarily result from the N-acyl-FB catalyzed by yCerS, rather than through direct binding of FB.
History
DepositionJan 26, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateNov 27, 2024-
Current statusNov 27, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_38858.png

Downloads & links

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Map

FileDownload / File: emd_38858.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 274.432 Å		1.07 Å/pix.
x 256 pix.
= 274.432 Å		1.07 Å/pix.
x 256 pix.
= 274.432 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.072 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.38
Minimum - Maximum-3.1078296 - 4.180544
Average (Standard dev.)0.0012258613 (±0.0874237)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 274.432 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_38858_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_38858_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Lac1-Lip1 complex

EntireName: Lac1-Lip1 complex
Components
  • Complex: Lac1-Lip1 complex
    • Protein or peptide: Ceramide synthase LAC1
    • Protein or peptide: Ceramide synthase subunit LIP1
  • Ligand: (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE

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Supramolecule #1: Lac1-Lip1 complex

SupramoleculeName: Lac1-Lip1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)

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Macromolecule #1: Ceramide synthase LAC1

MacromoleculeName: Ceramide synthase LAC1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: very-long-chain ceramide synthase
Source (natural)Organism: Saccharomyces cerevisiae S288C (yeast)
Molecular weightTheoretical: 50.289082 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSTIKPSPSN NNLKVRSRPR RKSSIGKIDL GDTVPSLGTM FETKESKTAA KRRMQRLSEA TKNDSDLVKK IWFSFREISY RHAWIAPLM ILIAVYSAYF TSGNTTKTNV LHRFVAVSYQ IGDTNAYGKG INDLCFVFYY MIFFTFLREF LMDVVIRPFA I RLHVTSKH ...String:
MSTIKPSPSN NNLKVRSRPR RKSSIGKIDL GDTVPSLGTM FETKESKTAA KRRMQRLSEA TKNDSDLVKK IWFSFREISY RHAWIAPLM ILIAVYSAYF TSGNTTKTNV LHRFVAVSYQ IGDTNAYGKG INDLCFVFYY MIFFTFLREF LMDVVIRPFA I RLHVTSKH RIKRIMEQMY AIFYTGVSGP FGIYCMYHSD LWFFNTKAMY RTYPDFTNPF LFKVFYLGQA AFWAQQACIL VL QLEKPRK DHNELTFHHI VTLLLIWSSY VFHFTKMGLP IYITMDVSDF LLSFSKTLNY LDSGLAFFSF AIFVVAWIYL RHY INLKIL WSVLTQFRTE GNYVLNFATQ QYKCWISLPI VFVLIGALQL VNLYWLFLIF RVLYRILWRG ILKDDRSDSE SDEE SDESS TTPTDSTPTK KDILEDYKDD DDK

UniProtKB: Ceramide synthase LAC1

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Macromolecule #2: Ceramide synthase subunit LIP1

MacromoleculeName: Ceramide synthase subunit LIP1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae S288C (yeast)
Molecular weightTheoretical: 17.228682 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MSQPTPIITT KSAAKPKPKI FNLFRVCFIS LLLIAAVEYF KYGTRINYEW FHCTPIKEPQ SGSVIKLWAR GGPSCDKRGE YKTIVKRIT RDYEPNDEHL SFCIIENDNV PPVHYPIHED KGEPGYVAYV GYDTDSELVQ ELCADSTIYH M

UniProtKB: Ceramide synthase subunit LIP1

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Macromolecule #3: (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-...

MacromoleculeName: (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE
type: ligand / ID: 3 / Number of copies: 8 / Formula: 6PL
Molecular weightTheoretical: 763.1 Da
Chemical component information

ChemComp-6PL:
(4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE / phospholipid*YM

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (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: 1.0 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: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 159061
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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