Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.
Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
FEBS Lett. 2020 Dec;594(23):4012-4034. doi: 10.1002/1873-3468.13947. Epub 2020 Oct 16.
The ABCG2 protein has a key role in the transport of a wide range of structurally dissimilar endo- and xenobiotics in the human body, especially in the tissue barriers and the metabolizing or secreting organs. The human ABCG2 gene harbors a high number of polymorphisms and mutations, which may significantly modulate its expression and function. Recent high-resolution structural data, complemented with molecular dynamic simulations, may significantly help to understand intramolecular movements and substrate handling, as well as the effects of mutations on the membrane transporter function of ABCG2. As reviewed here, structural alterations may result not only in direct alterations in drug binding and transporter activity, but also in improper folding or problems in the carefully regulated process of trafficking, including vesicular transport, endocytosis, recycling, and degradation. Here, we also review the clinical importance of altered ABCG2 expression and function in general drug metabolism, cancer multidrug resistance, and impaired uric acid excretion, leading to gout.
ABCG2 蛋白在人体中广泛运输结构不同的内源性和外源性物质中起着关键作用，特别是在组织屏障和代谢或分泌器官中。人类 ABCG2 基因含有大量的多态性和突变，这可能显著调节其表达和功能。最近的高分辨率结构数据，辅以分子动力学模拟，可能有助于理解分子内运动和底物处理，以及突变对 ABCG2 膜转运蛋白功能的影响。正如这里所综述的，结构改变不仅可能导致药物结合和转运体活性的直接改变，还可能导致折叠不当或在包括囊泡运输、内吞作用、回收和降解在内的精心调控的运输过程中出现问题。在这里，我们还综述了 ABCG2 表达和功能改变在一般药物代谢、癌症多药耐药性和尿酸排泄受损导致痛风中的临床重要性。
