期刊
NATURE
卷 526, 期 7573, 页码 397-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14909
关键词
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资金
- Knut and Alice Wallenberg Foundation
- Royal Society
- BBSRC [BB/G02325/1]
- ERATO Human Receptor Crystallography Project of the Japan Science and Technology Agency (JST)
- Research Acceleration Program of the JST
- Targeted Proteins Research Program of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- MEXT [22570114]
- MEXT
- Wellcome Trust at the Diamond Light Source Limited [062164/Z/00/Z]
- Centre for Biomembrane Research (CBR) - Swedish Foundation for Strategic Research
- Human Frontiers Postdoctoral fellowship
- EMBO through Young Investigator Program (YIP)
- Grants-in-Aid for Scientific Research [15H04338, 24108007, 25711004, 26102725, 15K06968] Funding Source: KAKEN
- Biotechnology and Biological Sciences Research Council [BB/G023425/1] Funding Source: researchfish
- BBSRC [BB/G023425/1] Funding Source: UKRI
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 tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures 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. On the basis of 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 Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a 'gated-pore' transport mechanism in such monosaccharide transporters.
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