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- PDB-8jyl: Acyl-ACP Synthetase structure bound to C10-AMS -

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Basic information

Entry
Database: PDB / ID: 8jyl
TitleAcyl-ACP Synthetase structure bound to C10-AMS
ComponentsAcyl-acyl carrier protein synthetase
KeywordsLIGASE / Acyl-ACP synthetase / Tool enzyme / CYTOSOLIC PROTEIN
Function / homology
Function and homology information


ligase activity, forming carbon-sulfur bonds
Similarity search - Function
: / ANL, N-terminal domain / AMP-binding enzyme C-terminal domain / AMP-binding enzyme, C-terminal domain / AMP-dependent synthetase/ligase / AMP-binding enzyme / AMP-binding enzyme, C-terminal domain superfamily
Similarity search - Domain/homology
: / Acyl-acyl carrier protein synthetase
Similarity search - Component
Biological speciesVibrio harveyi (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.33 Å
AuthorsHuang, H. / Chang, S. / Huang, M. / Zhang, H. / Zhou, C. / Zhang, X. / Feng, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32125003 China
CitationJournal: PLoS Pathog / Year: 2024
Title: An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.
Authors: Haomin Huang / Shenghai Chang / Tao Cui / Man Huang / Jiuxin Qu / Huimin Zhang / Ting Lu / Xing Zhang / Chun Zhou / Youjun Feng /
Abstract: Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), ...Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 Å) and C10-AMP intermediate (2.19 Å) in addition to its apo form (2.53 Å). Apart from our measurements for C10-AMS' Ki value of around 0.6 μM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.
History
DepositionJul 3, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2025Group: 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.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Acyl-acyl carrier protein synthetase
B: Acyl-acyl carrier protein synthetase
C: Acyl-acyl carrier protein synthetase
D: Acyl-acyl carrier protein synthetase
E: Acyl-acyl carrier protein synthetase
F: Acyl-acyl carrier protein synthetase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)365,44818
Polymers362,2996
Non-polymers3,14912
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Acyl-acyl carrier protein synthetase


Mass: 60383.102 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vibrio harveyi (bacteria) / Gene: aasS / Production host: Escherichia coli (E. coli) / References: UniProt: Q00IB3
#2: Chemical
ChemComp-VUL / [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl N-decanoylsulfamate


Mass: 500.569 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C20H32N6O7S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg / 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: Acyl-ACP Synthetase bound to C10-AMS / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Vibrio harveyi (bacteria)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
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: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.33 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 212195 / Symmetry type: POINT

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