9CFP
Cryo-EM structure of S. aureus TarGH in complex with AMP-PNP and targocil-II
This is a non-PDB format compatible entry.
Summary for 9CFP
| Entry DOI | 10.2210/pdb9cfp/pdb |
| Related | 9CFL |
| EMDB information | 45554 |
| Descriptor | Transport permease protein, Teichoic acids export ATP-binding protein TagH, Targocil-II, ... (6 entities in total) |
| Functional Keywords | abc transporter, teichoic acid, bacteria, membrane protein |
| Biological source | Staphylococcus aureus More |
| Total number of polymer chains | 4 |
| Total formula weight | 130114.98 |
| Authors | Peters, S.C.,Worrall, L.J.,Strynadka, N.C.J. (deposition date: 2024-06-27, release date: 2025-04-23) |
| Primary citation | Li, F.K.K.,Peters, S.C.,Worrall, L.J.,Sun, T.,Hu, J.,Vuckovic, M.,Farha, M.,Palacios, A.,Caveney, N.A.,Brown, E.D.,Strynadka, N.C.J. Cryo-EM analyses unveil details of mechanism and targocil-II mediated inhibition of S. aureus WTA transporter TarGH. Nat Commun, 16:3224-3224, 2025 Cited by PubMed 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 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. PubMed: 40185711DOI: 10.1038/s41467-025-58202-w PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.9 Å) |
Structure validation
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