Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions.

最近几篇关键论文揭示了对人ABCG2膜蛋白（一种具有药理学意义的转运蛋白）的原子级结构见解。尽管有大量的结构数据，但尚未阐明各种结构上不同的ABCG2底物的跨膜运动途径和转运蛋白的生理脂质调节。此处介绍的复杂分子动力学模拟可能会为理解底物转运过程及其受胆固醇调节的步骤提供突破。我们的分析揭示了除中心结合位点以外的药物结合腔，并描绘了具有可变结构的底物的假定的动态转运途径。我们发现膜胆固醇通过促进细胞质蛋白区域的封闭来加速药物运输。由于ABCG2存在于所有主要的生物屏障和药物代谢器官中，影响许多临床应用药物的药代动力学，并在尿酸挤出中起关键作用，因此该信息可能会大大促进对临床上重要的底物特征和药物-药物相互作用。