The conformational transition pathways of ATP-binding cassette transporter BtuCD revealed by targeted molecular dynamics simulation.
The conformational transition pathways of ATP-binding cassette transporter BtuCD revealed by targeted molecular dynamics simulation.
复制标题
靶向分子动力学模拟揭示 ATP 结合盒转运蛋白 BtuCD 的构象转变途径
DOI：
10.1371/journal.pone.0030465
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Weng J;Fan K;Wang W
BtuCD是大肠杆菌中ATP结合盒转运蛋白的成员，其通过利用ATP水解的能量将维生素B12输入细胞。BtuCD及其同源蛋白HI 1470/1在不同构象状态下的晶体结构支持“交替进入”机制，该机制提出了底物转运途径在跨膜结构域（TMD）处在面向外和面向内状态之间的构象转变。在TMD的构象转变被认为是耦合的ATP水解/结合驱动的细胞质核苷酸结合结构域（NBD）的运动。在这项研究中，我们进行了有针对性的分子动力学（MD）模拟，探索BtuCD进口商的构象转变的原子细节。发现NBD的构象运动引发了从外向内（O→I）的转变。随后的重定向的基板易位途径在TMD开始与关闭的周质门，随后由开放的胞质门在构象转变的最后阶段，由于广泛的疏水相互作用，在这个区域，与单向运输的基板的功能要求一致。BtuCD-F的反向内向外向（I→O）转变表现出构象转变途径的内在多样性和显著的结构不对称性，表明BtuCD-F的不对称晶体结构是这一过程的中间状态。
BtuCD is a member of the ATP-binding cassette transporters in Escherichia coli that imports vitamin B12 into the cell by utilizing the energy of ATP hydrolysis. Crystal structures of BtuCD and its homologous protein HI1470/1 in various conformational states support the “alternating access” mechanism which proposes the conformational transitions of the substrate translocation pathway at transmembrane domain (TMD) between the outward-facing and inward-facing states. The conformational transition at TMD is assumed to couple with the movement of the cytoplasmic nucleotide-binding domains (NBDs) driven by ATP hydrolysis/binding. In this study, we performed targeted molecular dynamics (MD) simulations to explore the atomic details of the conformational transitions of BtuCD importer. The outward-facing to inward-facing (O→I) transition was found to be initiated by the conformational movement of NBDs. The subsequent reorientation of the substrate translocation pathway at TMD began with the closing of the periplasmic gate, followed by the opening of the cytoplamic gate in the last stage of the conformational transition due to the extensive hydrophobic interactions at this region, consistent with the functional requirement of unidirectional transport of the substrates. The reverse inward-facing to outward-facing (I→O) transition was found to exhibit intrinsic diversity of the conformational transition pathways and significant structural asymmetry, suggesting that the asymmetric crystal structure of BtuCD-F is an intermediate state in this process.