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首页> 外文期刊>Biochemistry >Unilateral access regulation: Ground state dynamics of the Pseudomonas aeruginosa outer membrane efflux duct OprM
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Unilateral access regulation: Ground state dynamics of the Pseudomonas aeruginosa outer membrane efflux duct OprM

机译：单边通道调节：铜绿假单胞菌外膜外排导管OprM的基态动力学

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Acting as an efflux duct in the MexA-MexB-OprM multidrug efflux pump, OprM plays a major role in the antibiotic resistance capability of Pseudomonas aeruginosa, trafficking substrates through the outer cell membrane. Whereas the available crystal structures showed restricted OprM access on both ends, the underlying gating mechanism is not yet fully understood. To gain insight into the functional mechanism of OprM access regulation, we conducted a series of five independent, unbiased molecular dynamics simulations, computing 200 ns dynamics samples of the wild-type protein in a phospholipid membrane/150 mM NaCl water environment. On the extracellular side, OprM opens and closes freely under the simulated conditions, suggesting the absence of a gating mechanism on this side of the isolated protein. On the periplasmic side, we observe an opening of the tip regions at Val408 and to a lesser degree Asp416 located 1.5 nm further into the channel, leading to OprM end conformations being up to 3 and 1.4 times, respectively, more open than the asymmetric crystal structure. If our simulations are correct, our findings imply that periplasmic gating involves only the Asp416 region and that in vivo additional components, absent in our simulation, might be required for periplasmic gating if the observed opening trend near Asp416 is not negligible. In addition to that,we identified in each monomer a previously unreported sodium binding site in the channel interior coordinated by Asp171 and Asp230 whose functional role remains to be investigated.
机译：作为MexA-MexB-OprM多药外排泵中的外排导管，OprM在铜绿假单胞菌的抗药性中起主要作用，通过外细胞膜转运底物。尽管可用的晶体结构在两端均显示出受限的OprM通道，但尚未完全了解潜在的门控机制。为了深入了解OprM访问调控的功能机制，我们进行了一系列五个独立，无偏的分子动力学模拟，计算了磷脂膜/ 150 mM NaCl水环境中野生型蛋白质的200 ns动力学样品。在细胞外，OprM在模拟条件下可自由打开和关闭，表明分离的蛋白质这一侧没有门控机制。在周质方面，我们观察到Val408处的末端区域开放，并在距离通道1.5 nm处的较小程度的Asp416开放，导致OprM末端构象分别比不对称晶体开放分别高3倍和1.4倍。结构体。如果我们的模拟是正确的，我们的发现暗示周质门控仅涉及Asp416区域，如果不能忽略附近Asp416附近的开放趋势，周质门控可能需要体内不存在的其他组件。除此之外，我们在每个单体中确定了通道内部以前未报告的钠结合位点，该位点由Asp171和Asp230协同作用，其功能作用尚待研究。

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