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- EMDB-38375: Structure of acyltransferase GWT1 in complex with manogepix(APX001A) -

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Basic information

Entry
Database: EMDB / ID: EMD-38375
TitleStructure of acyltransferase GWT1 in complex with manogepix(APX001A)
Map data
Sample
  • Complex: Complex of GWT1 and inhibitor APX001A
    • Protein or peptide: GPI-anchored wall transfer protein 1
  • Ligand: 3-[3-[[4-(pyridin-2-yloxymethyl)phenyl]methyl]-1,2-oxazol-5-yl]pyridin-2-amine
Keywordsacyltransferase / MEMBRANE PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


glucosaminyl-phosphatidylinositol O-acyltransferase activity / Synthesis of glycosylphosphatidylinositol (GPI) / Transferases; Acyltransferases / GPI anchor biosynthetic process / nuclear outer membrane-endoplasmic reticulum membrane network / endoplasmic reticulum membrane / endoplasmic reticulum / membrane
Similarity search - Function
Phosphatidylinositol anchor biosynthesis protein PIGW/GWT1 / GWT1
Similarity search - Domain/homology
GPI-anchored wall transfer protein 1
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsDai XL / Li JL / Liu XZ / Deng D / Wang X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Structural insights into the inhibition mechanism of fungal GWT1 by manogepix.
Authors: Xinli Dai / Xuanzhong Liu / Jialu Li / Hui Chen / Chuangye Yan / Yaozong Li / Hanmin Liu / Dong Deng / Xiang Wang /
Abstract: Glycosylphosphatidylinositol (GPI) acyltransferase is crucial for the synthesis of GPI-anchored proteins. Targeting the fungal glycosylphosphatidylinositol acyltransferase GWT1 by manogepix is a ...Glycosylphosphatidylinositol (GPI) acyltransferase is crucial for the synthesis of GPI-anchored proteins. Targeting the fungal glycosylphosphatidylinositol acyltransferase GWT1 by manogepix is a promising antifungal strategy. However, the inhibitory mechanism of manogepix remains unclear. Here, we present cryo-EM structures of yeast GWT1 bound to the substrate (palmitoyl-CoA) and inhibitor (manogepix) at 3.3 Å and 3.5 Å, respectively. GWT1 adopts a unique fold with 13 transmembrane (TM) helixes. The palmitoyl-CoA inserts into the chamber among TM4, 5, 6, 7, and 12. The crucial residues (D145 and K155) located on the loop between TM4 and TM5 potentially bind to the GPI precursor, contributing to substrate recognition and catalysis, respectively. The antifungal drug, manogepix, occupies the hydrophobic cavity of the palmitoyl-CoA binding site, suggesting a competitive inhibitory mechanism. Structural analysis of resistance mutations elucidates the drug specificity and selectivity. These findings pave the way for the development of potent and selective antifungal drugs targeting GWT1.
History
DepositionDec 19, 2023-
Header (metadata) releaseOct 2, 2024-
Map releaseOct 2, 2024-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38375.png

Downloads & links

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Map

FileDownload / File: emd_38375.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.1367097 - 1.5315496
Average (Standard dev.)0.0009143286 (±0.024956567)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_38375_msk_1.map
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Half map: #2

Fileemd_38375_half_map_1.map
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Half map: #1

Fileemd_38375_half_map_2.map
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Sample components

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Entire : Complex of GWT1 and inhibitor APX001A

EntireName: Complex of GWT1 and inhibitor APX001A
Components
  • Complex: Complex of GWT1 and inhibitor APX001A
    • Protein or peptide: GPI-anchored wall transfer protein 1
  • Ligand: 3-[3-[[4-(pyridin-2-yloxymethyl)phenyl]methyl]-1,2-oxazol-5-yl]pyridin-2-amine

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Supramolecule #1: Complex of GWT1 and inhibitor APX001A

SupramoleculeName: Complex of GWT1 and inhibitor APX001A / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)

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Macromolecule #1: GPI-anchored wall transfer protein 1

MacromoleculeName: GPI-anchored wall transfer protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: Transferases; Acyltransferases
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Molecular weightTheoretical: 55.511918 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSTLKQRKED FVTGLNGGSI TEINAVTSIA LVTYISWNLL KNSNLMPPGI SSVQYIIDFA LNWVALLLSI TIYASEPYLL NTLILLPCL LAFIYGKFTS SSKPSNPIYN KKKMITQRFQ LEKKPYITAY RGGMLILTAI AILAVDFPIF PRRFAKVETW G TSLMDLGV ...String:
MSTLKQRKED FVTGLNGGSI TEINAVTSIA LVTYISWNLL KNSNLMPPGI SSVQYIIDFA LNWVALLLSI TIYASEPYLL NTLILLPCL LAFIYGKFTS SSKPSNPIYN KKKMITQRFQ LEKKPYITAY RGGMLILTAI AILAVDFPIF PRRFAKVETW G TSLMDLGV GSFVFSNGIV SSRALLKNLS LKSKPSFLKN AFNALKSGGT LLFLGLLRLF FVKNLEYQEH VTEYGVHWNF FI TLSLLPL VLTFIDPVTR MVPRCSIAIF ISCIYEWLLL KDDRTLNFLI LADRNCFFSA NREGIFSFLG YCSIFLWGQN TGF YLLGNK PTLNNLYKPS TQDVVAASKK SSTWDYWTSV TPLSGLCIWS TIFLVISQLV FQYHPYSVSR RFANLPYTLW VITY NLLFL TGYCLTDKIF GNSSEYYKVA ECLESINSNG LFLFLLANVS TGLVNMSMVT IDSSPLKSFL VLLAYCSFIA VISVF LYRK RIFIKL

UniProtKB: GPI-anchored wall transfer protein 1

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Macromolecule #2: 3-[3-[[4-(pyridin-2-yloxymethyl)phenyl]methyl]-1,2-oxazol-5-yl]py...

MacromoleculeName: 3-[3-[[4-(pyridin-2-yloxymethyl)phenyl]methyl]-1,2-oxazol-5-yl]pyridin-2-amine
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1LVI
Molecular weightTheoretical: 358.393 Da

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k 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: 1.8 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 252957
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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