PDF(Pubmed)
Abstract：
ATP-binding cassette transporters represent a superfamily of dynamic membrane-based proteins with diverse yet common functions such as use of ATP hydrolysis to efflux substrates across cellular membranes. Three major transporters-P-glycoprotein (P-gp or ABCB1), multidrug resistance protein 1 (MRP1 or ABCC1), and breast cancer resistance protein (BCRP or ABCG2) are notoriously involved in therapy resistance in cancer patients. Despite exhaustive individual characterizations of each of these transporters, there is a lack of understanding in terms of the functional role of mutations in substrate binding and efflux, leading to drug resistance. We analyzed clinical variations reported in endometrial cancers for these transporters. For ABCB1, the majority of key mutations were present in the membrane-facing region, followed by the drug transport channel and ATP-binding regions. Similarly, for ABCG2, the majority of key mutations were located in the membrane-facing region, followed by the ATP-binding region and drug transport channel, thus highlighting the importance of membrane-mediated drug recruitment and efflux in ABCB1 and ABCG2. On the other hand, for ABCC1, the majority of key mutations were present in the inactive nucleotide-binding domain, followed by the drug transport channel and membrane-facing regions, highlighting the importance of the inactive nucleotide-binding domain in facilitating indirect drug efflux in ABCC1. The identified key mutations in endometrial cancer and mapped common mutations present across different types of cancers in ABCB1, ABCC1, and ABCG2 will facilitate the design and discovery of inhibitors targeting unexplored structural regions of these transporters and re-engineering of these transporters to tackle chemoresistance.
摘要：
ATP结合盒转运蛋白代表动态膜基蛋白的超家族，具有多种但常见的功能，例如使用ATP水解使底物流出细胞膜。三种主要转运蛋白-P-糖蛋白（P-gp或ABCB1），多药耐药蛋白1（MRP1或ABCC1），乳腺癌耐药蛋白（BCRP或ABCG2）与癌症患者的治疗耐药有关。尽管这些转运蛋白中的每一个都有详尽的个体特征，对突变在底物结合和外排中的功能作用缺乏了解，导致抗药性。我们分析了子宫内膜癌中报道的这些转运蛋白的临床变异。对于ABCB1，大多数关键突变存在于面向膜的区域，其次是药物转运通道和ATP结合区。同样，对于ABCG2，大多数关键突变位于面向膜的区域，其次是ATP结合区和药物转运通道，从而突出了ABCB1和ABCG2中膜介导的药物募集和外排的重要性。另一方面,对于ABCC1，大多数关键突变存在于无活性的核苷酸结合域中，其次是药物运输通道和面向膜的区域，强调非活性核苷酸结合结构域在促进ABCC1中间接药物流出中的重要性。确定的子宫内膜癌中的关键突变以及ABCB1，ABCC1和ABCG2中不同类型癌症中存在的常见突变将有助于设计和发现靶向这些转运蛋白的未开发结构区域的抑制剂，并重新设计这些转运蛋白以解决化学抗性。
