Structure of the human lipid exporter ABCB4 in a lipid environment.,Nature Structural & Molecular Biology

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Structure of the human lipid exporter ABCB4 in a lipid environment.
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2019-12-23 , DOI: 10.1038/s41594-019-0354-3
Jeppe A Olsen _{1,

2} , Amer Alam _{1,

3} , Julia Kowal ₁ , Bruno Stieger ₄ , Kaspar P Locher ₁

Affiliation

ABCB4 is an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or drug-induced liver injury. We determined the cryo-EM structure of nanodisc-reconstituted human ABCB4 trapped in an ATP-bound state at a resolution of 3.2 Å. The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg2+. The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but we observed a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound. This indicates a state following substrate release but prior to ATP hydrolysis. Our results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters.

中文翻译：

脂质环境中人类脂质输出者 ABCB4 的结构。

ABCB4 是一种 ATP 结合盒转运蛋白，可将磷脂酰胆碱挤出到肝脏的胆小管中。其功能障碍或药物抑制可导致严重的慢性肝病或药物性肝损伤。我们确定了以 3.2 Å 的分辨率捕获在 ATP 结合状态中的纳米圆盘重组人 ABCB4 的冷冻电镜结构。核苷酸结合结构域形成包含两个结合的 ATP 分子的闭合构象，但只有一个 ATP 酶位点含有结合的 Mg2+。跨膜结构域在脂质双层水平采用塌陷构象，但我们在细胞质膜边界水平观察到一个大的、亲水的和完全封闭的空腔，没有配体结合。这表明在底物释放之后但在 ATP 水解之前的状态。

更新日期：2019-12-23

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