Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, UK.
Nature. 2011 Oct 5;478(7369):408-11. doi: 10.1038/nature10450.
High cholesterol levels greatly increase the risk of cardiovascular disease. About 50 per cent of cholesterol is eliminated from the body by its conversion into bile acids. However, bile acids released from the bile duct are constantly recycled, being reabsorbed in the intestine by the apical sodium-dependent bile acid transporter (ASBT, also known as SLC10A2). It has been shown in animal models that plasma cholesterol levels are considerably lowered by specific inhibitors of ASBT, and ASBT is thus a target for hypercholesterolaemia drugs. Here we report the crystal structure of a bacterial homologue of ASBT from Neisseria meningitidis (ASBT(NM)) at 2.2 Å. ASBT(NM) contains two inverted structural repeats of five transmembrane helices. A core domain of six helices harbours two sodium ions, and the remaining four helices pack in a row to form a flat, 'panel'-like domain. Overall, the architecture of the protein is remarkably similar to the sodium/proton antiporter NhaA, despite having no detectable sequence homology. The ASBT(NM) structure was captured with the substrate taurocholate present, bound between the core and panel domains in a large, inward-facing, hydrophobic cavity. Residues near this cavity have been shown to affect the binding of specific inhibitors of human ASBT. The position of the taurocholate molecule, together with the molecular architecture, suggests the rudiments of a possible transport mechanism.
高胆固醇水平大大增加了心血管疾病的风险。大约 50%的胆固醇通过转化为胆汁酸从体内排出。然而，从胆管释放的胆汁酸不断循环，通过肠腔顶端钠依赖胆汁酸转运蛋白（ASBT，也称为 SLC10A2）被重新吸收。动物模型表明，ASBT 的特异性抑制剂可显著降低血浆胆固醇水平，因此 ASBT 是治疗高胆固醇血症药物的靶点。在这里，我们报道了脑膜炎奈瑟菌（ASBT（NM））的细菌同源物的晶体结构，分辨率为 2.2Å。ASBT（NM）包含两个五个跨膜螺旋的反向结构重复。由六个螺旋组成的核心结构域含有两个钠离子，其余四个螺旋排列成一排，形成一个平坦的“面板”样结构域。总的来说，尽管没有检测到序列同源性，但该蛋白质的结构与钠/质子反向转运蛋白 NhaA 非常相似。ASBT（NM）结构的捕获是在存在底物牛磺胆酸钠的情况下进行的，该分子结合在核心和面板结构域之间的一个大的、面向内的疏水性腔中。该腔附近的残基已被证明会影响人 ASBT 特异性抑制剂的结合。牛磺胆酸钠分子的位置以及分子结构表明了可能的运输机制的基本原理。
