胆固醇水平升高会显著增加患动脉粥样硬化和心血管疾病的风险。胆固醇是在转换成胆汁酸之后从身体中被消除的,所以能够在小肠中重新吸收胆汁酸的“顶端钠依赖性胆汁酸运输因子”是降低胆固醇疗法的一个主要药物作用目标。现在,结合到其胆汁酸基质上的ASBT的一个细菌同源物的X-射线晶体结构已被确定。该基质(牛磺胆酸)存在于这一蛋白的“核心”区域和“面板”区域之间一个很大的憎水空腔中,从而为这一重要生物分子提出一个可能的运输机制。(生物谷 Bioon.com)
doi:10.1038/nature10450
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Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT
Nien-Jen Hu, So Iwata, Alexander D. Cameron & David Drew
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 (ASBTNM) at 2.2 Å. ASBTNM 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 ASBTNM 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