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Structure and mechanism of the mammalian fructose transporter GLUT5

DOI: 10.1038/nature14909 DOI Help
PMID: 26416735 PMID Help

Authors: Norimichi Nomura (Kyoto University) , Gregory Verdon (Imperial College London; Diamond Light Source) , Haejoo Kang (Imperial College London) , Tatsuro Shimamura (Kyoto University) , Yayoi Nomura (Kyoto University) , Yo Sonoda (Imperial College London) , Saba Abdul Hussein (Stockholm University) , Aziz Qureshi (Stockholm University) , Mathieu Coincon (Stockholm University) , Yumi Sato (Kyoto University) , Hitomi Abe (Kyoto University) , Yoshiko Nakada-nakura (Kyoto University) , Tomoya Hino (Kyoto University) , Takatoshi Arakawa (Kyoto University) , Osamu Kusano-arai (University of Tokyo) , Hiroko Iwanari (University of Tokyo) , Takeshi Murata (Kyoto University) , Takuya Kobayashi (Kyoto University) , Takao Hamakubo (University of Tokyo) , Michihiro Kasahara (Teikyo University) , So Iwata (Diamond Light Source; Kyoto University) , David Drew ((Imperial College London))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 526 , PAGES 397 - 401

State: Published (Approved)
Published: October 2015

Abstract: 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.

Journal Keywords: X-ray crystallography; Transporters

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Membrane Protein Laboratory (MPL)
Instruments: I02-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 19/02/2016 11:58

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