1] Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK [2] Biomedical Sciences Research Complex, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK.
1] Biomedical Sciences Research Complex, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK [2] Department of Microbiology, College of Resource and Environment Science, Sichuan Agriculture University, Yaan 625000, China.
Nature. 2014 Jul 3;511(7507):52-6. doi: 10.1038/nature13464. Epub 2014 Jun 18.
Lipopolysaccharide (LPS) is essential for most Gram-negative bacteria and has crucial roles in protection of the bacteria from harsh environments and toxic compounds, including antibiotics. Seven LPS transport proteins (that is, LptA-LptG) form a trans-envelope protein complex responsible for the transport of LPS from the inner membrane to the outer membrane, the mechanism for which is poorly understood. Here we report the first crystal structure of the unique integral membrane LPS translocon LptD-LptE complex. LptD forms a novel 26-stranded β-barrel, which is to our knowledge the largest β-barrel reported so far. LptE adopts a roll-like structure located inside the barrel of LptD to form an unprecedented two-protein 'barrel and plug' architecture. The structure, molecular dynamics simulations and functional assays suggest that the hydrophilic O-antigen and the core oligosaccharide of the LPS may pass through the barrel and the lipid A of the LPS may be inserted into the outer leaflet of the outer membrane through a lateral opening between strands β1 and β26 of LptD. These findings not only help us to understand important aspects of bacterial outer membrane biogenesis, but also have significant potential for the development of novel drugs against multi-drug resistant pathogenic bacteria.
脂多糖 (LPS) 对大多数革兰氏阴性菌至关重要，在保护细菌免受恶劣环境和有毒化合物（包括抗生素）的侵害方面发挥着关键作用。七种 LPS 转运蛋白（即 LptA-LptG）形成一个跨膜蛋白复合物，负责将 LPS 从内膜转运到外膜，其机制尚不清楚。在这里，我们报告了第一个独特的完整膜 LPS 转运蛋白 LptD-LptE 复合物的晶体结构。LptD 形成了一个新型的 26 股β-桶，据我们所知，这是迄今为止报道的最大的β-桶。LptE 采用滚轴样结构位于 LptD 的桶内，形成了前所未有的双蛋白“桶和塞”结构。结构、分子动力学模拟和功能分析表明，LPS 的亲水性 O-抗原和核心寡糖可能穿过桶，而 LPS 的脂多糖可能通过 LptD 的β1 和β26 之间的侧开口插入外膜的外叶。这些发现不仅有助于我们理解细菌外膜生物发生的重要方面，而且对开发针对多药耐药性病原菌的新型药物具有重要潜力。
