Exploring movement and energy in human P-glycoprotein conformational rearrangement.
Exploring movement and energy in human P-glycoprotein conformational rearrangement.
复制标题
探索人类 P-糖蛋白构象重排中的运动和能量。
DOI：
10.1080/07391102.2018.1461133
复制
发表时间：
2018
影响因子：
4.4
通讯作者：
Li Chunhua
中科院分区：
文献类型：
--
作者：
Zhang Yue;Gong Weikang;Wang Yan;Liu Yang;Li Chunhua
人P-糖蛋白（P-gp）是一种ATP结合盒转运蛋白，可以将多种抗癌药物输出到肿瘤细胞外。它的过度表达是肿瘤细胞产生多药耐药性（MDR）的主要原因之一。已证实，在基质传输过程中，P-gp经历了从向内状态到向外状态的大规模结构重排。然而，核苷酸结合域（NBD）如何控制跨膜域（TMD）以面向外的状态向周质开放的机制尚未完全表征。在此，进行了有针对性的分子动力学模拟来探索人 P-gp 的构象重排。结果表明，变构过程以耦合方式进行，首先由NBDs驱动，然后传递到TMDs的细胞质部分，最后传递到周质部分。轨迹显示，除了平移运动外，NBD 还进行旋转运动，主要发生在 xyplane 上，并确保形成正确的 ATP 结合袋。对TMD和NBD的六个结构片段（cICL）之间相互作用能的分析表明，它们细微的能量差异在导致跨膜螺旋的周质部分以既定方向和适当幅度相互分离方面发挥着重要作用。这一结论可以在一定程度上解释人类P-gp的两个实验现象。这些研究对人类 P-gp 重排过程进行了详细的探索，并对 P-gp 转变过程中 TMD 重新定向提供了能量洞察。
Human P-glycoprotein (P-gp), a kind of ATP-Binding Cassette transporter, can export a diverse variety of anti-cancer drugs out of the tumor cell. Its overexpression is one of the main reasons for the multidrug resistance (MDR) of tumor cells. It has been confirmed that during the substrate transport process, P-gp experiences a large-scale structural rearrangement from the inward- to outward-facing states. However, the mechanism of how the nucleotide-binding domains (NBDs) control the transmembrane domains (TMDs) to open towards the periplasm in the outward-facing state has not yet been fully characterized. Herein, targeted molecular dynamics simulations were performed to explore the conformational rearrangement of human P-gp. The results show that the allosteric process proceeds in a coupled way, and first the transition is driven by the NBDs, and then transmitted to the cytoplasmic parts of TMDs, finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement, which mainly occurs inxyplane and ensures the formation of the correct ATP-binding pockets. The analyses on the interaction energies between the six structure segments (cICLs) from the TMDs and NBDs reveal that their subtle energy differences play an important role in causing the periplasmic parts of the transmembrane helices to separate from each other in the established directions and in appropriate amplitudes. This conclusion can explain the two experimental phenomena about human P-gp in some extent. These studies have provided a detailed exploration into human P-gp rearrangement process and given an energy insight into the TMD reorientation during P-gp transition.