Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT.
Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT.
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DOI：
10.1038/nature10450
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发表时间：
2011-10-05
期刊：
影响因子：
64.8
通讯作者：
Drew, David
中科院分区：
文献类型：
--
作者：
Hu, Nien-Jen;Iwata, So;Cameron, Alexander D.;Drew, David
高胆固醇水平会大大增加患心血管疾病的风险。通过转化为胆汁酸，约50%的胆固醇被排出体外。然而，从胆管释放的胆汁酸不断再循环，通过顶端钠依赖性胆汁酸转运蛋白（ASBT）在肠道中被重吸收。在动物模型中已经显示，ASBT的特异性抑制剂显著降低血浆胆固醇水平，因此ASBT是高胆固醇血症药物的靶点。在这里，我们描述了来自脑膜炎奈瑟氏球菌（ASBTNM）的ASBT细菌同源物在2.2 Å的晶体结构。ASBTNM含有两个五个跨膜螺旋的反向结构重复。六个螺旋的核心结构域含有两个钠离子，而其余的螺旋形成一个面板状结构域。总的来说，蛋白质的结构与钠-质子反向转运蛋白NhaA非常相似，尽管没有可检测到的序列同源性。胆汁酸分子位于大的疏水空腔中的核心和Panel结构域之间。已显示靠近该空腔的残基影响人ASBT的特异性抑制剂的结合。胆汁酸的位置与分子结构一起表明了可能的转运机制的雏形。
High cholesterol levels greatly increase the risk of cardiovascular disease. By its conversion into bile acids, about 50% of cholesterol is eliminated from the body. However bile acids released from the bile duct are constantly recycled, being reabsorbed in the intestine via the Apical Sodium dependent Bile acid Transporter (ASBT). It has been shown in animal models that plasma cholesterol levels are significantly lowered by specific inhibitors of ASBT, thus ASBT is a target for hypercholesterolemia drugs. Here, we describe the crystal structure of a bacterial homologue of ASBT from Neisseria meningitidis (ASBTNM) at 2.2Å. ASBTNM contains two inverted structural repeats of five transmembrane helices. A Core domain of six helices harbours two sodium ions while the remaining helices form a Panel-like domain. Overall the architecture of the protein is remarkably similar to the sodium-proton antiporter NhaA despite no detectable sequence homology. A bile acid molecule is situated between the Core and Panel domains in a large hydrophobic cavity. Residues near to this cavity have been shown to affect the binding of specific inhibitors of human ASBT. The position of the bile acid together with the molecular architecture suggests the rudiments of a possible transport mechanism.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
14.8
作者：
Drew, David;Newstead, Simon;Iwata, So
通讯作者：
Iwata, So
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G
影响因子：
4.5
作者：
Hagenbuch, B;Dawson, P
通讯作者：
Dawson, P
DOI：
10.1073/pnas.0804659105
发表时间：
2008-07-29
影响因子：
11.1
作者：
Forrest, Lucy R.;Zhang, Yuan-Wei;Rudnick, Gary
通讯作者：
Rudnick, Gary