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- PDB-9mhz: Cryo-EM structure of S. aureus TarGH in complex with Targocil-II ... -

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Basic information

Entry
Database: PDB / ID: 9mhz
TitleCryo-EM structure of S. aureus TarGH in complex with Targocil-II and ATP-gamma-S in a catalytically incompetent conformation
Components
  • Teichoic acids export ATP-binding protein TagH
  • Transport permease protein
KeywordsMEMBRANE PROTEIN / ABC transporter / teichoic acid / bacteria
Function / homology
Function and homology information


ABC-type teichoic-acid transporter / ABC-type teichoic acid transporter activity / lipopolysaccharide transport / ABC-type transporter activity / ATP hydrolysis activity / ATP binding / plasma membrane
Similarity search - Function
Teichoic acids export ATP-binding protein tagH. / ABC transporter, teichoic acids export TagH-like / : / : / ABC transporter integral membrane type-2 domain profile. / ABC-2 type transporter / ABC-2 type transporter / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter ...Teichoic acids export ATP-binding protein tagH. / ABC transporter, teichoic acids export TagH-like / : / : / ABC transporter integral membrane type-2 domain profile. / ABC-2 type transporter / ABC-2 type transporter / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / Lauryl Maltose Neopentyl Glycol / Transport permease protein / Teichoic acids export ATP-binding protein TagH
Similarity search - Component
Biological speciesStaphylococcus aureus (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsPeters, S.C. / Worrall, L.J. / Strynadka, N.C.J.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: Nat Commun / Year: 2025
Title: Cryo-EM analyses unveil details of mechanism and targocil-II mediated inhibition of S. aureus WTA transporter TarGH.
Authors: Franco K K Li / Shaun C Peters / Liam J Worrall / Tianjun Sun / Jinhong Hu / Marija Vuckovic / Maya Farha / Armando Palacios / Nathanael A Caveney / Eric D Brown / Natalie C J Strynadka /
Abstract: Wall teichoic acid (WTA) is a polyol phosphate polymer that covalently decorates peptidoglycan of gram-positive bacteria, including Staphylococcus aureus. Central to WTA biosynthesis is flipping of ...Wall teichoic acid (WTA) is a polyol phosphate polymer that covalently decorates peptidoglycan of gram-positive bacteria, including Staphylococcus aureus. Central to WTA biosynthesis is flipping of lipid-linked precursors across the cell membrane by TarGH, a type V ABC transporter. Here, we present cryo-EM structures of S. aureus TarGH in the presence of targocil-II, a promising small-molecule lead with β-lactam antibiotic synergistic action. Targocil-II binds to the extracellular dimerisation interface of TarG, we suggest mimicking flipped but not yet released substrate. In absence of targocil-II and in complex with ATP analogue ATPγS, determined at 2.3 Å resolution, the ATPase active site is allosterically inhibited. This is due to a so far undescribed D-loop conformation, potentially minimizing spurious ATP hydrolysis in the absence of substrate. Targocil-II binding comparatively causes local and remote conformational changes through to the TarH active site, with the D-loop now optimal for ATP hydrolysis. These structures suggest an ability to modulate ATP hydrolysis in a WTA substrate dependent manner and a jammed ATPase cycle as the basis of the observed inhibition by targocil-II. The molecular insights provide an unprecedented basis for development of TarGH targeted therapeutics for treatment of multidrug-resistant S. aureus and other gram-positive bacterial infections.
History
DepositionDec 12, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 23, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transport permease protein
B: Teichoic acids export ATP-binding protein TagH
D: Teichoic acids export ATP-binding protein TagH
C: Transport permease protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,15912
Polymers128,0944
Non-polymers4,0658
Water1448
1


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

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Components

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Protein , 2 types, 4 molecules ACBD

#1: Protein Transport permease protein


Mass: 34240.527 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus (bacteria) / Gene: tagG, SAUSA300_0625 / Production host: Lactococcus lactis (lactic acid bacteria) / References: UniProt: A0A0H2XIF1
#2: Protein Teichoic acids export ATP-binding protein TagH


Mass: 29806.553 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus (bacteria) / Gene: tagH, SAUSA300_0624 / Production host: Lactococcus lactis (lactic acid bacteria)
References: UniProt: Q2FJ01, ABC-type teichoic-acid transporter

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Non-polymers , 5 types, 16 molecules

#3: Chemical ChemComp-AV0 / Lauryl Maltose Neopentyl Glycol / 2,2-didecylpropane-1,3-bis-b-D-maltopyranoside / 2-decyl-2-{[(4-O-alpha-D-glucopyranosyl-beta-D-glucopyranosyl)oxy]methyl}dodecyl4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside


Mass: 1005.188 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C47H88O22 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-A1AV9 / Targocil-II / 1-{[3-(4-chlorophenyl)-5,9-dimethyl-7-oxo-7H-furo[3,2-g][1]benzopyran-6-yl]acetyl}-D-proline


Mass: 479.909 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H22ClNO6 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-AGS / PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-GAMMA-S / ADENOSINE 5'-(3-THIOTRIPHOSPHATE) / ADENOSINE 5'-(GAMMA-THIOTRIPHOSPHATE) / ADENOSINE-5'-DIPHOSPHATE MONOTHIOPHOSPHATE


Mass: 523.247 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C10H16N5O12P3S / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP-gamma-S, energy-carrying molecule analogue*YM
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: H2O

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Details

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: TarGH / Type: COMPLEX / Details: Hetero tetramer TarG2H2 / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Staphylococcus aureus (bacteria)
Source (recombinant)Organism: Lactococcus lactis (lactic acid bacteria)
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 121556 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0059142
ELECTRON MICROSCOPYf_angle_d0.69912368
ELECTRON MICROSCOPYf_dihedral_angle_d10.911228
ELECTRON MICROSCOPYf_chiral_restr0.0461382
ELECTRON MICROSCOPYf_plane_restr0.0061488

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