Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors
Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors
复制标题
DOI：
10.1126/science.aav9406
复制
发表时间：
2019-05-17
期刊：
影响因子：
56.9
通讯作者：
Mchaourab, Hassane S.
中科院分区：
文献类型：
--
作者：
Dastvan, Reza;Mishra, Smriti;Mchaourab, Hassane S.
ATP结合盒亚家族B成员1（ABCB 1）多药转运蛋白P-糖蛋白在人体内清除外源性物质中起着重要作用，并与癌症对化疗的耐药性有关。我们使用双电子电子共振光谱揭示了多底物刺激P-糖蛋白腺苷5 '-三磷酸（ATP）水解的基础，并阐明了底物和抑制剂如何不同地影响其转运功能。我们的研究结果表明，底物诱导的ATP水解的加速与稳定的高能量，后ATP水解状态，其特征在于结构不对称的核苷酸结合位点。相比之下，这种状态在无底物循环中不稳定，并且通过有利于结构对称的核苷酸结合位点的高亲和力抑制剂。与以前的数据一起，我们的研究结果导致底物和抑制剂耦合到P-糖蛋白的一般模型。
The ATP-binding cassette subfamily B member 1 (ABCB1) multidrug transporter P-glycoprotein plays a central role in clearance of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. We used double electron electron resonance spectroscopy to uncover the basis of stimulation of P-glycoprotein adenosine 5'-triphosphate (ATP) hydrolysis by multiple substrates and illuminate how substrates and inhibitors differentially affect its transport function. Our results reveal that substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites. By contrast, this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites. Together with previous data, our findings lead to a general model of substrate and inhibitor coupling to P-glycoprotein.