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- EMDB-35008: Acyl-ACP Synthetase structure -

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Basic information

Entry
Database: EMDB / ID: EMD-35008
TitleAcyl-ACP Synthetase structure
Map data
Sample
  • Complex: Acyl-ACP Synthetase
    • Protein or peptide: Acyl-acyl carrier protein synthetase
KeywordsAcyl-ACP synthetase / Tool enzyme / CYTOSOLIC PROTEIN
Function / homologyligase activity, forming carbon-sulfur bonds / : / 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 / Acyl-acyl carrier protein synthetase
Function and homology information
Biological speciesVibrio harveyi (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.53 Å
AuthorsHuang H / Wang C / Chang S / Cui T / Xu Y / Zhang H / Zhou C / Zhang X / Feng Y
Funding support China, 1 items
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
DepositionDec 20, 2022-
Header (metadata) releaseDec 27, 2023-
Map releaseDec 27, 2023-
UpdateJan 15, 2025-
Current statusJan 15, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_35008.png

Downloads & links

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Map

FileDownload / File: emd_35008.map.gz / Format: CCP4 / Size: 125 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.)
1.01 Å/pix.
x 320 pix.
= 324.48 Å		1.01 Å/pix.
x 320 pix.
= 324.48 Å		1.01 Å/pix.
x 320 pix.
= 324.48 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.24
Minimum - Maximum-1.7236264 - 3.1817014
Average (Standard dev.)0.000120699995 (±0.07798993)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 324.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35008_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_35008_half_map_2.map
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Sample components

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Entire : Acyl-ACP Synthetase

EntireName: Acyl-ACP Synthetase
Components
  • Complex: Acyl-ACP Synthetase
    • Protein or peptide: Acyl-acyl carrier protein synthetase

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Supramolecule #1: Acyl-ACP Synthetase

SupramoleculeName: Acyl-ACP Synthetase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Vibrio harveyi (bacteria)

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Macromolecule #1: Acyl-acyl carrier protein synthetase

MacromoleculeName: Acyl-acyl carrier protein synthetase / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Vibrio harveyi (bacteria)
Molecular weightTheoretical: 60.496258 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MNQYVNDPSN YQLLIKNLLF SPVAFNPEQE IVYANHRRHS YKTFHDRVRQ FANALTKMGV KKGDTVAVMD YDSHRYLECY FAIPMIGAK LHMINVRLSP EQILYTIDHA EDDIILIHEE FLPILDQIKG RIDTVTRYVV LRDDEECEYE RLLEQESTEY N FPDFDENT ...String:
MNQYVNDPSN YQLLIKNLLF SPVAFNPEQE IVYANHRRHS YKTFHDRVRQ FANALTKMGV KKGDTVAVMD YDSHRYLECY FAIPMIGAK LHMINVRLSP EQILYTIDHA EDDIILIHEE FLPILDQIKG RIDTVTRYVV LRDDEECEYE RLLEQESTEY N FPDFDENT VATTFYTTGT TGFPKGVFFT HRQLVLHTMG ILSTIGTNAS QGRLHQGDIY MPITPMFHVH AWGLPYMATM LG VKQVYPG KYVPDVLLNL IEQEKVTFSH CVPTILHLLL SSPKSKAMDF SGWKVVIGGA ALPKALCKSA LERDIDVFAG YGM SETGPI LSIVQLTPEQ LELDVDQQAE YRSKTGKKVA LVEAYIVDED MNKLPHDGET AGEIVVRAPW LTPNYYKDNK NSKA LWRGG YLHTGDVAHI DDEGFIKITD RVKDMIKISG EWVSSLELED ILHQHQSVSE VAVIGMPHNK WGEVPLALVT LKEDA QVTE KELLGFAKDF INKGILAREA LLLKVKIVDE IAKTSVGKVD KKELRKLHL

UniProtKB: Acyl-acyl carrier protein synthetase

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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

Concentration15 mg/mL
BufferpH: 8
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: 2.5 µm / Nominal defocus min: 1.5 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: 2.53 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 539382
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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