The ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid.,Nature Communications

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The ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid.
Nature Communications ( IF 14.7 ) Pub Date : 2019-11-28 , DOI: 10.1038/s41467-019-13302-2
Narakorn Khunweeraphong ₁ , Daniel Szöllősi ₂ , Thomas Stockner ₂ , Karl Kuchler ₁

Affiliation

The human ATP-binding cassette transporter ABCG2 is a key to anticancer resistance and physiological detoxification. However, the molecular mechanism of substrate transport remains enigmatic. A hydrophobic di-leucine motif in the ABCG2 core separates a large intracellular cavity from a smaller upper cavity. We show that the di-leucine motif acts as a valve that controls drug extrusion. Moreover, the extracellular structure engages the re-entry helix and all extracellular loops to form a roof architecture on top of the upper cavity. Disulfide bridges and a salt bridge limit roof flexibility, but provide a lid-like function to control drug release. We propose that drug translocation from the central to the upper cavities through the valve is driven by a squeezing motion, suggesting that ABCG2 operates similar to a peristaltic pump. Finally, the roof contains essential residues, offering therapeutic options to block ABCG2 by either targeting the valve or essential residues in the roof.

中文翻译：

ABCG2多药转运蛋白是由阀门和细胞外盖封闭的泵。

人ATP结合盒转运蛋白ABCG2是抗癌性和生理解毒的关键。但是，底物转运的分子机制仍然是个谜。ABCG2核心中的疏水性双亮氨酸基序将较大的细胞内腔与较小的上腔分隔开。我们表明，双亮氨酸基序充当控制药物挤出的阀门。此外，细胞外结构与折返螺旋和所有细胞外环接合，在上腔顶部形成屋顶结构。二硫键和盐键限制了屋顶的柔韧性，但提供了类似盖的功能来控制药物的释放。我们提出，药物通过挤压运动从中央腔到上腔的移位是由挤压运动驱动的，这表明ABCG2的操作类似于蠕动泵。最后，

更新日期：2019-11-29

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