Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein.
Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein.
复制标题
配体进入，可延展结合和诱导螺旋蛋白的螺旋运动的快照。
DOI：
10.1107/s1399004715000978
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Chang G
中科院分区：
文献类型：
--
作者：
Szewczyk P;Tao H;McGrath AP;Villaluz M;Rees SD;Lee SC;Doshi R;Urbatsch IL;Zhang Q;Chang G
p -糖蛋白与一系列工程配体的共晶结构揭示了多种配体结合模式，转运体外表面的配体结合位点以及可能与ATP水解偶联的构象变化。p糖蛋白（P-gp）是一种具有重要临床和药理意义的转运蛋白。对P-gp及其同源物的一些结构研究已经提供了对其转运周期的见解，但关于P-gp如何识别不同底物以及底物结合如何与ATP水解耦合的问题仍然存在。本文提出了四种新的P-gp共晶结构和一系列合理设计的配体。观察到，某些配体的结合，包括atp水解刺激剂，在第四个跨膜螺旋中产生了很大的构象变化，其定位可能将信号传递到核苷酸结合结构域。本文还描述了P-gp表面上一个面向膜内小叶的新的配体结合位点，为疏水药物和脂质进入P-gp的机制提供了重要的见解。这些结果在理解P-gp和相关转运体如何结合和输出大量代谢物、抗生素和临床批准的药物和管道药物方面取得了重大进展。
Co-crystal structures of P-glycoprotein with a series of engineered ligands reveal multiple ligand-binding modes, a ligand-binding site on the outer surface of the transporter and a conformational change that may couple to ATP hydrolysis. P-glycoprotein (P-gp) is a transporter of great clinical and pharmacological significance. Several structural studies of P-gp and its homologs have provided insights into its transport cycle, but questions remain regarding how P-gp recognizes diverse substrates and how substrate binding is coupled to ATP hydrolysis. Here, four new P-gp co-crystal structures with a series of rationally designed ligands are presented. It is observed that the binding of certain ligands, including an ATP-hydrolysis stimulator, produces a large conformational change in the fourth transmembrane helix, which is positioned to potentially transmit a signal to the nucleotide-binding domains. A new ligand-binding site on the surface of P-gp facing the inner leaflet of the membrane is also described, providing vital insights regarding the entry mechanism of hydrophobic drugs and lipids into P-gp. These results represent significant advances in the understanding of how P-gp and related transporters bind and export a plethora of metabolites, antibiotics and clinically approved and pipeline drugs.