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首页> 外文期刊>Biochemistry >Catalytic transitions in the human mdr1 P-glycoprotein drug binding sites
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Catalytic transitions in the human mdr1 P-glycoprotein drug binding sites

机译：人类mdr1 P-糖蛋白药物结合位点的催化转变

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Multidrug resistance proteins that belong to the ATP-binding cassette family like the human P-glycoprotein (ABCB1 or Pgp) are responsible for many failed cancer and antiviral chemotherapies because these membrane transporters remove the chemotherapeutics from the targeted cells. Understanding the details of the catalytic mechanism of Pgp is therefore critical to the development of inhibitors that might overcome these resistances. In this work, targeted molecular dynamics techniques were used to elucidate catalytically relevant structures of Pgp. Crystal structures of homologues in four different conformations were used as intermediate targets in the dynamics simulations. Transitions from conformations that were wide open to the cytoplasm to transition state conformations that were wide open to the extracellular space were studied. Twenty-six nonredundant transitional protein structures were identified from these targeted molecular dynamics simulations using evolutionary structure analyses. Coupled movement of nucleotide binding domains (NBDs) and transmembrane domains (TMDs) that form the drug binding cavities were observed. Pronounced twisting of the NBDs as they approached each other as well as the quantification of a dramatic opening of the TMDs to the extracellular space as the ATP hydrolysis transition state was reached were observed. Docking interactions of 21 known transport ligands or inhibitors were analyzed with each of the 26 transitional structures. Many of the docking results obtained here were validated by previously published biochemical determinations. As the ATP hydrolysis transition state was approached, drug docking in the extracellular half of the transmembrane domains seemed to be destabilized as transport ligand exit gates opened to the extracellular space.
机译：像人P-糖蛋白（ABCB1或Pgp）一样，属于ATP结合盒家族的多药抗性蛋白质是导致许多失败的癌症和抗病毒化学疗法的原因，因为这些膜转运蛋白从靶细胞中去除了化学疗法。因此，了解Pgp催化机理的细节对于开发可能克服这些抗性的抑制剂至关重要。在这项工作中，有针对性的分子动力学技术被用来阐明Pgp的催化相关结构。在动力学模拟中，四种不同构象的同系物的晶体结构被用作中间目标。研究了从向细胞质敞开的构象向向细胞外空间敞开的过渡态构象的转变。使用进化结构分析从这些目标分子动力学模拟中鉴定出二十六个非冗余过渡蛋白结构。观察到形成药物结合腔的核苷酸结合域（NBD）和跨膜域（TMD）的耦合运动。观察到NBD彼此接近时发生了明显的扭曲，并观察到随着到达ATP水解转变状态，TMD急剧向细胞外空间开放。用26种过渡结构中的每一种分析了21种已知的运输配体或抑制剂的对接相互作用。此处获得的许多对接结果已通过先前发表的生物化学测定结果进行了验证。随着接近ATP水解转变状态，由于转运配体出口门向细胞外空间打开，药物对接跨膜结构域的一半似乎不稳定。

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    《Biochemistry》 |2012年第25期|共17页
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    Wise J.G.;

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