4TW1

Crystal structure of the octameric pore complex of the Staphylococcus aureus Bi-component Toxin LukGH

4TW1 の概要

• エントリーDOI: 10.2210/pdb4tw1/pdb
• 分子名称: Possible leukocidin subunit (3 entities in total)
• 機能のキーワード: octamer leukocidin pore-forming toxin, toxin
• 由来する生物種: Staphylococcus aureus; 詳細
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 588065.75

構造登録者

Logan, D.T.,Hakansson, M.,Saline, M.,Kimbung, R.,Badarau, A.,Rouha, H.,Nagy, E. (登録日: 2014-06-29, 公開日: 2014-11-12, 最終更新日: 2023-12-20)

主引用文献

Badarau, A.,Rouha, H.,Malafa, S.,Logan, D.T.,Hakansson, M.,Stulik, L.,Dolezilkova, I.,Teubenbacher, A.,Gross, K.,Maierhofer, B.,Weber, S.,Jagerhofer, M.,Hoffman, D.,Nagy, E.
Structure-Function Analysis of Heterodimer Formation, Oligomerization, and Receptor Binding of the Staphylococcus aureus Bi-component Toxin LukGH.
J.Biol.Chem., 290:142-156, 2015

PubMed Abstract: The bi-component leukocidins of Staphylococcus aureus are important virulence factors that lyse human phagocytic cells and contribute to immune evasion. The γ-hemolysins (HlgAB and HlgCB) and Panton-Valentine leukocidin (PVL or LukSF) were shown to assemble from soluble subunits into membrane-bound oligomers on the surface of target cells, creating barrel-like pore structures that lead to cell lysis. LukGH is the most distantly related member of this toxin family, sharing only 30-40% amino acid sequence identity with the others. We observed that, unlike other leukocidin subunits, recombinant LukH and LukG had low solubility and were unable to bind to target cells, unless both components were present. Using biolayer interferometry and intrinsic tryptophan fluorescence we detected binding of LukH to LukG in solution with an affinity in the low nanomolar range and dynamic light scattering measurements confirmed formation of a heterodimer. We elucidated the structure of LukGH by x-ray crystallography at 2.8-Å resolution. This revealed an octameric structure that strongly resembles that reported for HlgAB, but with important structural differences. Structure guided mutagenesis studies demonstrated that three salt bridges, not found in other bi-component leukocidins, are essential for dimer formation in solution and receptor binding. We detected weak binding of LukH, but not LukG, to the cellular receptor CD11b by biolayer interferometry, suggesting that in common with other members of this toxin family, the S-component has the primary contact role with the receptor. These new insights provide the basis for novel strategies to counteract this powerful toxin and Staphylococcus aureus pathogenesis.

PubMed: 25371205
DOI: 10.1074/jbc.M114.598110

実験手法

X-RAY DIFFRACTION (2.8 Å)