Conformational dynamics and putative substrate extrusion pathways of the N-glycosylated outer membrane factor CmeC from Campylobacter jejuni.
Conformational dynamics and putative substrate extrusion pathways of the N-glycosylated outer membrane factor CmeC from Campylobacter jejuni.
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从弯曲杆菌空肠杆菌的N-糖基化外膜CMEC CMEC的构象动力学和推定的底物挤出途径。
DOI：
10.1371/journal.pcbi.1010841
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发表时间：
2023-01
影响因子：
4.3
通讯作者：
Khalid, Syma
中科院分区：
文献类型：
--
作者：
Newman, Kahlan;Khalid, Syma
外排机制CmeABC的外膜因子CmeC在赋予空肠弯曲菌抗生素和胆汁抗性中起重要作用。奇怪的是，蛋白质是N-糖基化的，聚糖在该系统的有效功能中起着关键作用。在这项工作中，我们采用原子平衡分子动力学模拟的CmeC在一个代表性的模型的C。空肠外膜的蛋白质及其相关聚糖的动力学。我们表明，聚糖是更构象不稳定比以前认为的。CmeC的细胞外环自由地访问开放和闭合状态，表明在这一侧不存在门控机制，而狭窄的周质入口保持紧密闭合，通过与溶剂化阳离子的配位来调节。我们确定了几个阳离子结合位点的蛋白质的内表面上。此外，我们使用转向分子动力学模拟来阐明胆汁酸和大环内酯类抗生素的易位途径。这些和额外的平衡模拟表明，阴离子胆汁酸利用多价阳离子爬上酸性残基的梯子，内衬的蛋白质的内表面。空肠弯曲菌是一种革兰氏阴性菌，是胃肠炎的主要原因。感染也与一些自身免疫性疾病的发展有关。因此，它具有重要的生物医学意义。细菌外排泵将废物和有害化学物质（包括抗生素）从细胞内挤出到细胞外环境，从而阻碍了抗菌治疗。C. jejuni是跨细胞包膜的CmeABC蛋白复合物。外膜因子CmeC在赋予C.空肠。我们已经使用CmeC的分子动力学模拟来模拟胆汁酸和抗生素通过这种糖基化蛋白质移动的途径。我们确定了几个阳离子结合位点内的蛋白质的内腔，并表明，阴离子胆汁酸利用多价阳离子爬梯子的酸性残基，行内表面的蛋白质。
The outer membrane factor CmeC of the efflux machinery CmeABC plays an important role in conferring antibiotic and bile resistance to Campylobacter jejuni. Curiously, the protein is N-glycosylated, with the glycans playing a key role in the effective function of this system. In this work we have employed atomistic equilibrium molecular dynamics simulations of CmeC in a representative model of the C. jejuni outer membrane to characterise the dynamics of the protein and its associated glycans. We show that the glycans are more conformationally labile than had previously been thought. The extracellular loops of CmeC visit the open and closed states freely suggesting the absence of a gating mechanism on this side, while the narrow periplasmic entrance remains tightly closed, regulated via coordination to solvated cations. We identify several cation binding sites on the interior surface of the protein. Additionally, we used steered molecular dynamics simulations to elucidate translocation pathways for a bile acid and a macrolide antibiotic. These, and additional equilibrium simulations suggest that the anionic bile acid utilises multivalent cations to climb the ladder of acidic residues that line the interior surface of the protein. Campylobacter jejuni is a Gram-negative bacterium that is a major cause of gastroenteritis. Infection is also associated with the development of some auto-immune conditions. Therefore, it is of key biomedical importance. Bacterial efflux pumps extrude waste and harmful chemicals, including antibiotics from inside the cell to the extracellular environment, thus providing an impediment to antibacterial treatments. The major efflux system of C. jejuni is the cell envelope spanning CmeABC protein complex. The outer membrane factor CmeC plays an important role in conferring antibiotic and bile resistance to C. jejuni. We have used molecular dynamics simulations of CmeC to characterise the pathways via which a bile acid and an antibiotic move through this glycosylated protein. We identify several cation-binding sites within the lumen of the protein and show that the anionic bile acid utilises multivalent cations to climb the ladder of acidic residues that line the interior surface of the protein.
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影响因子：
5.2
作者：
ENDTZ, HP;RUIJS, GJ;MOUTON, RP
通讯作者：
MOUTON, RP
DOI：
10.1021/la504407v
发表时间：
2015
期刊：
Langmuir : the ACS journal of surfaces and colloids
影响因子：
--
作者：
Clifton LA;Skoda MW;Le Brun AP;Ciesielski F;Kuzmenko I;Holt SA;Lakey JH
通讯作者：
Lakey JH
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
6.3
作者：
BERENDSEN, HJC;VANDERSPOEL, D;VANDRUNEN, R
通讯作者：
VANDRUNEN, R
DOI：
10.1016/j.bbagen.2017.07.014
发表时间：
2017-11-01
影响因子：
3
作者：
Gilardi, A.;Bhamidimarri, S. P.;Windshuegel, B.
通讯作者：
Windshuegel, B.