Structural data on ABCG5/G8 and ABCG2 reveal a unique molecular architecture for subfamily G ATP‐binding cassette (ABCG) transporters and disclose putative substrate‐binding sites. ABCG5/G8 and ABCG2 appear to use several unique structural motifs to execute transport, including the triple helical bundles, the membrane‐embedded polar relay, the re‐entry helices, and a hydrophobic valve. Interestingly, ABCG2 shows extreme substrate promiscuity, whereas ABCG5/G8 transports only sterol molecules. ABCG2 structures suggest a large internal cavity, serving as a binding region for substrates and inhibitors, while mutational and pharmacological analyses support the notion of multiple binding sites. By contrast, ABCG5/G8 shows a collapsed cavity of insufficient size to hold substrates. Indeed, mutational analyses indicate a sterol‐binding site at the hydrophobic interface between the transporter and the lipid bilayer. In this review, we highlight key differences and similarities between ABCG2 and ABCG5/G8 structures. We further discuss the relevance of distinct and shared structural features in the context of their physiological functions. Finally, we elaborate on how ABCG2 and ABCG5/G8 could pave the way for studies on other ABCG transporters.

中文翻译：

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挑剔的 ABCG5/G8 和混杂的 ABCG2——脂肪饮食和药物毒性的故事

ABCG5/G8 和 ABCG2 的结构数据揭示了亚家族 G ATP 结合盒 (ABCG) 转运蛋白的独特分子结构，并揭示了推定的底物结合位点。ABCG5/G8 和 ABCG2 似乎使用几个独特的结构基序来执行运输，包括三螺旋束、膜嵌入极性中继、再入螺旋和疏水阀。有趣的是，ABCG2 显示出极端的底物混杂性，而 ABCG5/G8 仅运输甾醇分子。ABCG2 结构表明有一个大的内腔，作为底物和抑制剂的结合区域，而突变和药理学分析支持多个结合位点的概念。相比之下，ABCG5/G8 显示出一个塌陷的空腔，其尺寸不足以容纳基板。的确，突变分析表明在转运蛋白和脂质双层之间的疏水界面处存在甾醇结合位点。在这篇综述中，我们强调了 ABCG2 和 ABCG5/G8 结构之间的主要区别和相似之处。我们进一步讨论了不同和共享结构特征在其生理功能背景下的相关性。最后，我们详细阐述了 ABCG2 和 ABCG5/G8 如何为其他 ABCG 转运蛋白的研究铺平道路。