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首页> 外文期刊>Journal of Molecular Biology >Structural Basis of Drug Recognition by the Multidrug Transporter ABCG2
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Structural Basis of Drug Recognition by the Multidrug Transporter ABCG2

机译：多药转运仪ABCG2的药物识别的结构基础

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ABCG2 is an ATP-binding cassette (ABC) transporter whose function affects the pharmacokinetics of drugs and contributes to multidrug resistance of cancer cells. While its interaction with the endogenous substrate estrone-3-sulfate (E1S) has been elucidated at a structural level, the recognition and recruitment of exogenous compounds is not understood at sufficiently high resolution. Here we present three cryo-EM structures of nanodisc-reconstituted, human ABCG2 bound to anticancer drugs tariquidar, topotecan and mitoxantrone. To enable structural insight at high resolution, we used Fab fragments of the ABCG2-specific monoclonal antibody 5D3, which binds to the external side of the transporter but does not interfere with drug-induced stimulation of ATPase activity. We observed that the binding pocket of ABCG2 can accommodate a single tariquidar molecule in a C-shaped conformation, similar to one of the two tariquidar molecules bound to ABCB1, where tariquidar acts as an inhibitor. We also found single copies of topotecan and mitoxantrone bound between key phenylalanine residues. Mutagenesis experiments confirmed the functional importance of two residues in the binding pocket, F439 and N436. Using 3D variability analyses, we found a correlation between substrate binding and reduced dynamics of the nucleotide binding domains (NBDs), suggesting a structural explanation for drug-induced ATPase stimulation. Our findings provide additional insight into how ABCG2 differentiates between inhibitors and substrates and may guide a rational design of new modulators and substrates. (C) 2021 The Authors. Published by Elsevier Ltd.
机译：ABCG2是一种ATP结合盒（ABC）转运体，其功能影响药物的药代动力学，并促进癌细胞的多药耐药性。虽然其与内源性底物雌酮-3-硫酸酯（E1S）的相互作用已在结构水平上得到阐明，但外源化合物的识别和补充尚不清楚。在这里，我们提出了三种冷冻电镜结构的纳米盘重组，人ABCG2结合抗癌药物塔里克达尔，拓扑替康和米托蒽醌。为了实现高分辨率的结构洞察，我们使用了ABCG2特异性单克隆抗体5D3的Fab片段，该抗体结合到转运体的外侧，但不干扰药物诱导的ATP酶活性刺激。我们观察到ABCG2的结合囊可以容纳C形构象的单个tariquidar分子，类似于与ABCB1结合的两个tariquidar分子之一，其中tariquidar起到抑制剂的作用。我们还发现拓扑替康和米托蒽醌的单拷贝结合在关键苯丙氨酸残基之间。突变实验证实了结合袋中两个残基F439和N436的功能重要性。利用3D变异性分析，我们发现了底物结合和核苷酸结合域（NBD）动力学降低之间的相关性，这表明了药物诱导ATP酶刺激的结构解释。我们的发现为ABCG2如何区分抑制剂和底物提供了进一步的见解，并可能指导新调节剂和底物的合理设计。（c）作者2021。爱思唯尔有限公司出版。

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