膽固醇水平升高會(huì)顯著增加患動(dòng)脈粥樣硬化和心血管疾病的風(fēng)險(xiǎn),。膽固醇是在轉(zhuǎn)換成膽汁酸之后從身體中被消除的,，所以能夠在小腸中重新吸收膽汁酸的“頂端鈉依賴性膽汁酸運(yùn)輸因子”是降低膽固醇療法的一個(gè)主要藥物作用目標(biāo)。現(xiàn)在,，結(jié)合到其膽汁酸基質(zhì)上的ASBT的一個(gè)細(xì)菌同源物的X-射線晶體結(jié)構(gòu)已被確定,。該基質(zhì)（牛磺膽酸）存在于這一蛋白的“核心”區(qū)域和“面板”區(qū)域之間一個(gè)很大的憎水空腔中,，從而為這一重要生物分子提出一個(gè)可能的運(yùn)輸機(jī)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