Structural basis of small-molecule inhibition of human multidrug transporter ABCG2
Structural basis of small-molecule inhibition of human multidrug transporter ABCG2
复制标题
DOI：
10.1038/s41594-018-0049-1
复制
发表时间：
2018-04-01
影响因子：
16.8
通讯作者：
Locher, Kaspar P.
中科院分区：
文献类型：
--
作者：
Jackson, Scott M.;Manolaridis, Ioannis;Locher, Kaspar P.
ABCG2是一种三磷酸腺苷结合盒(ABC)转运蛋白，可保护组织免受外来生物的侵害，影响药物的药代动力学，并导致多药耐药。虽然已经开发了许多ABCG2的抑制剂和调节剂，但了解它们的构效关系需要高分辨率的结构洞察力。在这里，我们介绍了人ABCG2的冷冻EM结构，它与烟曲霉菌C相关抑制剂Ko143或多药耐药调节剂Tariquidar的合成衍生物结合。这两种化合物都结合在ABCG2的中心向内的空腔上，阻止底物的进入，防止ATP水解所需的构象变化。高分辨率允许整个转运蛋白的从头构建，也揭示了紧密结合的磷脂和胆固醇与跨膜结构域(TMD)的脂暴露表面相互作用。结合体外功能分析，对Ko143支架进行了广泛的化学修饰，揭示了ABCG2与该化合物家族相互作用的细节，为设计新型抑制剂和调节剂提供了基础。
ABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors and modulators of ABCG2 have been developed, understanding their structure-activity relationship requires high-resolution structural insight. Here, we present cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar. Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the transmembrane domains (TMDs). Extensive chemical modifications of the Ko143 scaffold combined with in vitro functional analyses revealed the details of ABCG2 interactions with this compound family and provide a basis for the design of novel inhibitors and modulators.