Opening of the ADP-bound active site in the ABC transporter ATPase dimer: Evidence for a constant contact, alternating sites model for the catalytic cycle
Opening of the ADP-bound active site in the ABC transporter ATPase dimer: Evidence for a constant contact, alternating sites model for the catalytic cycle
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DOI：
10.1002/prot.22250
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发表时间：
2009-05-01
影响因子：
2.9
通讯作者：
George, Anthony M.
中科院分区：
文献类型：
--
作者：
Jones, Peter M.;George, Anthony M.
ABC转运蛋白是普遍存在的ATP依赖性跨膜泵。ATP水解的核苷酸结合域（NBD）的跨膜结构域，导致allocrite易位的影响构象变化的机制仍然在很大程度上是未知的。这一机制的一个可能的方面是建议由以前的分子动力学模拟的MJ 0796 NBD二聚体，揭示了一种新的，核苷酸依赖的intrasubunit构象变化涉及的螺旋和催化亚结构域的相对旋转。在这里，我们发现，在四个五模拟的ADP/ATP结合的二聚体，在ADP结合的单体中的螺旋和催化子域的相对旋转的结果在ADP结合的活性位点的开放，可能足以或接近足以允许核苷酸交换。我们还观察到，在所有五个模拟的ADP/ATP结合的二聚体，密切接触的LSGGQ签名序列与ATP的γ-磷酸被削弱的亚单位内的ADP结合的单体的构象变化。我们讨论了这些结果如何支持一个恒定的接触模型的功能的NBD二聚体的开关模型，其中NBD的建议完全解离在催化循环。
ABC transporters are ubiquitous, ATP-dependent transmembrane pumps. The mechanism by which ATP hydrolysis in the nucleotide-binding domain (NBD) effects conformational changes in the transmembrane domain that lead to allocrite translocation remains largely unknown. A possible aspect of this mechanism was suggested by previous molecular dynamics simulations of the MJ0796 NBD dimer, which revealed a novel, nucleotide-dependent intrasubunit conformational change involving the relative rotation of the helical and catalytic subdomains. Here, we find that in four of five simulations of the ADP/ATP-bound dimer, the relative rotation of the helical and catalytic subdomains in the ADP-bound monomer results in opening of the ADP-bound active site, probably sufficient or close to sufficient to allow nucleotide exchange. We also observe that in all five simulations of the ADP/ATP-bound dimer, the intimate contact of the LSGGQ signature sequence with the ATP gamma-phosphate is weakened by the intrasubunit conformational change within the ADP-bound monomer. We discuss how these results support a constant contact model for the function of the NBD dimer in contrast to switch models, in which the NBDs are proposed to fully disassociate during the catalytic cycle.