Structure and mechanism of the mammalian fructose transporter GLUT5.
Structure and mechanism of the mammalian fructose transporter GLUT5.
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DOI：
10.1038/nature14909
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发表时间：
2015-10-15
期刊：
影响因子：
64.8
通讯作者：
Drew D
中科院分区：
文献类型：
--
作者：
Nomura N;Verdon G;Kang HJ;Shimamura T;Nomura Y;Sonoda Y;Hussien SA;Qureshi AA;Coincon M;Sato Y;Abe H;Nakada-Nakura Y;Hino T;Arakawa T;Kusano-Arai O;Iwanari H;Murata T;Kobayashi T;Hamakubo T;Kasahara M;Iwata S;Drew D
果糖转运蛋白 GLUT5 是易化葡萄糖转运蛋白家族的一种亚型，其活性的改变与 2 型糖尿病和肥胖等疾病有关。 GLUT5 在某些肿瘤细胞中也过度表达，抑制剂是治疗这些疾病的潜在药物。在这里，我们分别描述了褐家鼠和牛的 GLUT5 的晶体结构，分别为开放的向外和开放的向内构象。与其他同源单糖转运蛋白一样，GLUT5 具有主要的促进子超家族折叠。基于 GLUT5 和人类 GLUT1（一种普遍存在的葡萄糖转运蛋白）的向内结构的比较，我们表明单点突变足以将 GLUT5 的底物结合偏好从果糖转换为葡萄糖。 GLUT5 的无底物结构与 XylE 的封闭底物结合结构的比较表明，除了束的全局摇杆开关式重新定向之外，C 端束螺旋 TM 7 和 10 的局部不对称重排也是此类单糖转运蛋白中“门控孔”转运机制的基础。
The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is also overexpressed in certain tumor cells and inhibitors are potential drugs for these conditions. Here, we describe the crystal structure of GLUT5 from Rattus norvegicus and Bos taurus in open outward- and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. Based on a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of XylE suggests that, besides global rocker-switch like re-orientation of the bundles, local asymmetric rearrangements of C-terminal bundle helices TMs 7 and 10 underlie a “gated-pore” transport mechanism in such monosaccharide transporters.