Molecular basis for inhibiting human glucose transporters by exofacial inhibitors

被引:24
|
作者
Wang, Nan [1 ]
Zhang, Shuo [1 ]
Yuan, Yafei [1 ]
Xu, Hanwen [1 ]
Defossa, Elisabeth [2 ]
Matter, Hans [2 ]
Besenius, Melissa [2 ]
Derdau, Volker [2 ]
Dreyer, Matthias [2 ]
Halland, Nis [2 ]
He, Kaihui Hu [3 ]
Petry, Stefan [2 ]
Podeschwa, Michael [2 ]
Tennagels, Norbert [4 ]
Jiang, Xin [1 ,5 ]
Yan, Nieng [1 ,6 ]
机构
[1] Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Tsinghua Peking Joint Ctr Life Sci, State Key Lab Membrane Biol,Sch Life Sci, Beijing 100084, Peoples R China
[2] Sanofi Aventis Deutschland GmbH, R&D, Integrated Drug Discovery, Ind Pk Hochst, D-65926 Frankfurt, Germany
[3] Sanofi Aventis Deutschland GmbH, R&D, CMC Synthet Early Dev Analyt, Ind Pk Hochst, D-65926 Frankfurt, Germany
[4] Bayer AG, R&D, Pharmaceut, TA Endocrinol Metab & Reprod Hlth,DIU Exploratory, D-42096 Wuppertal, Germany
[5] Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia
[6] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA
基金
中国国家自然科学基金;
关键词
CRYSTAL-STRUCTURE; STRUCTURAL BASIS; GLUT; BINDING; MEMBRANE; SYSTEM; FAMILY; CANCER;
D O I
10.1038/s41467-022-30326-3
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Human glucose transporters (GLUTs) are responsible for cellular uptake of hexoses. Elevated expression of GLUTs, particularly GLUT1 and GLUT3, is required to fuel the hyperproliferation of cancer cells, making GLUT inhibitors potential anticancer therapeutics. Meanwhile, GLUT inhibitor-conjugated insulin is being explored to mitigate the hypoglycemia side effect of insulin therapy in type 1 diabetes. Reasoning that exofacial inhibitors of GLUT1/3 may be favored for therapeutic applications, we report here the engineering of a GLUT3 variant, designated GLUT3exo, that can be probed for screening and validating exofacial inhibitors. We identify an exofacial GLUT3 inhibitor SA47 and elucidate its mode of action by a 2.3 angstrom resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development. Human glucose transporters (GLUTs), particularly GLUT1 and GLUT3, are potential anticancer therapy targets. Here, Nan Wang et al. use an engineered GLUT 3 variant to identify an exofacial GLUT3 inhibitor, SA47, and elucidate the drug's inhibitory mechanism.
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页数:10
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