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- PDB-8xik: Structure of acyltransferase GWT1 in complex with manogepix(APX001A) -

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Basic information

Entry
Database: PDB / ID: 8xik
TitleStructure of acyltransferase GWT1 in complex with manogepix(APX001A)
ComponentsGPI-anchored wall transfer protein 1
KeywordsMEMBRANE PROTEIN/INHIBITOR / acyltransferase / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsDai, X.L. / Li, J.L. / Liu, X.Z. / Deng, D. / Wang, X.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 13, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.page_last / _citation.pdbx_database_id_PubMed ..._citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GPI-anchored wall transfer protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,8702
Polymers55,5121
Non-polymers3581
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein GPI-anchored wall transfer protein 1


Mass: 55511.918 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: GWT1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P47026, Transferases; Acyltransferases
#2: Chemical ChemComp-A1LVI / 3-[3-[[4-(pyridin-2-yloxymethyl)phenyl]methyl]-1,2-oxazol-5-yl]pyridin-2-amine


Mass: 358.393 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18N4O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: Complex of GWT1 and inhibitor APX001A / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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 FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 252957 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033830
ELECTRON MICROSCOPYf_angle_d0.5895214
ELECTRON MICROSCOPYf_dihedral_angle_d7.209515
ELECTRON MICROSCOPYf_chiral_restr0.037614
ELECTRON MICROSCOPYf_plane_restr0.006629

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