9CFP

Cryo-EM structure of S. aureus TarGH in complex with AMP-PNP and targocil-II

これはPDB形式変換不可エントリーです。

9CFP の概要

• エントリーDOI: 10.2210/pdb9cfp/pdb
• 関連するPDBエントリー: 9CFL
• EMDBエントリー: 45554
• 分子名称: Transport permease protein, Teichoic acids export ATP-binding protein TagH, Targocil-II, ... (6 entities in total)
• 機能のキーワード: abc transporter, teichoic acid, bacteria, membrane protein
• 由来する生物種: Staphylococcus aureus; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 130114.98

構造登録者

Peters, S.C.,Worrall, L.J.,Strynadka, N.C.J. (登録日: 2024-06-27, 公開日: 2025-04-23)

主引用文献

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

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: 40185711
DOI: 10.1038/s41467-025-58202-w

実験手法

ELECTRON MICROSCOPY (2.9 Å)