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首页> 外文期刊>Acta crystallographica. Section D, Biological crystallography. >Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein
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Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein

机译：配体的快照,听话的绑定和在22诱导螺旋运动

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摘要

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.
机译：22 (P-gp)是伟大的运输车临床和药理学意义。几个P-gp及其结构的研究同系物为其提供了见解运输周期,但问题仍在P-gp如何识别不同的基质和如何衬底耦合绑定到ATP水解。在这里,四个新P-gp co-crystal结构了一系列的合理设计配体提出了。特定的配体,包括一个ATP-hydrolysis刺激,产生大量的构象第四个跨膜螺旋的变化,定位潜在传输一个信号nucleotide-binding域。表面配体结合网站P-gp面临的内部传单膜也关于描述,提供了重要的见解条目的疏水性药物和脂质机制P-gp。了解P-gp和进步相关的转运蛋白绑定和大量出口代谢物,抗生素,临床诊断批准和管道的药物。

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