Dimer opening of the nucleotide binding domains of ABC transporters after ATP hydrolysis.
Dimer opening of the nucleotide binding domains of ABC transporters after ATP hydrolysis.
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DOI：
10.1529/biophysj.108.139444
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发表时间：
2008-12
影响因子：
3.4
通讯作者：
Po-Chao Wen;E. Tajkhorshid
中科院分区：
文献类型：
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作者：
Po-Chao Wen;E. Tajkhorshid
ABC 转运蛋白是最丰富的膜转运蛋白家族之一。该家族最常见的特征是高度保守的核苷酸结合域 (NBD)，它通过 ATP 的结合和水解来驱动运输过程。分子动力学模拟用于研究 ATP 水解在 NBD 中的影响。从与 ATP 结合的 MalK 闭合二聚体开始，构建了四个模拟系统，其中 ATP 或 ADP-P(i) 与两个核苷酸结合位点结合的所有可能组合均已构建，并使用平衡分子动力学进行模拟，每个系统约 70 ns。结果表明，NBD 二聚体的闭合形式只能通过两个结合的 ATP 分子来维持；换句话说，一个 ATP 的水解可以导致 NBD 二聚体的二聚体界面打开。此外，我们观察到开放是 ATP 水解成 ADP 和 P(i) 的直接效应，而不是水解产物的解离。此外，该开放是由 LSGGQ 基序从结合的核苷酸解离而触发的。在所有模拟系统中，在二聚体打开之前始终观察到亚稳态 ADP-P(i) 结合构象状态。
ABC transporters constitute one of the most abundant membrane transporter families. The most common feature shared in the family is the highly conserved nucleotide binding domains (NBDs) that drive the transport process through binding and hydrolysis of ATP. Molecular dynamics simulations are used to investigate the effect of ATP hydrolysis in the NBDs. Starting with the ATP-bound, closed dimer of MalK, four simulation systems with all possible combinations of ATP or ADP-P(i) bound to the two nucleotide binding sites are constructed and simulated with equilibrium molecular dynamics for approximately 70 ns each. The results suggest that the closed form of the NBD dimer can only be maintained with two bound ATP molecules; in other words, hydrolysis of one ATP can lead to the opening of the dimer interface of the NBD dimer. Furthermore, we observed that the opening is an immediate effect of hydrolysis of ATP into ADP and P(i) rather than the dissociation of hydrolysis products. In addition, the opening is mechanistically triggered by the dissociation of the LSGGQ motif from the bound nucleotide. A metastable ADP-P(i) bound conformational state is consistently observed before the dimer opening in all the simulation systems.