Molecular basis for inhibiting human glucose transporters by exofacial inhibitors

Nan Wang; Shuo Zhang; Yafei Yuan; Hanwen Xu; Elisabeth Defossa; Hans Matter; Melissa Besenius; Volker Derdau; Matthias Dreyer; Nis Halland; Kaihui Hu He; Stefan Petry; Michael Podeschwa; Norbert Tennagels; Xin Jiang; Nieng Yan

doi:10.1038/s41467-022-30326-3

Molecular basis for inhibiting human glucose transporters by exofacial inhibitors

Nan Wang, Shuo Zhang, Yafei Yuan, Hanwen Xu, Elisabeth Defossa, Hans Matter, Melissa Besenius, Volker Derdau, Matthias Dreyer, Nis Halland, Kaihui Hu He, Stefan Petry, Michael Podeschwa, Norbert Tennagels, Xin Jiang, Nieng Yan

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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 Å resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development.

Original language	English (US)
Article number	2632
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30326-3
State	Published - Dec 2022

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-022-30326-3

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title = "Molecular basis for inhibiting human glucose transporters by exofacial inhibitors",

abstract = "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 {\AA} resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development.",

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AU - Wang, Nan

AU - Zhang, Shuo

AU - Yuan, Yafei

AU - Xu, Hanwen

AU - Defossa, Elisabeth

AU - Matter, Hans

AU - Besenius, Melissa

AU - Derdau, Volker

AU - Dreyer, Matthias

AU - Halland, Nis

AU - He, Kaihui Hu

AU - Petry, Stefan

AU - Podeschwa, Michael

AU - Tennagels, Norbert

AU - Jiang, Xin

AU - Yan, Nieng

PY - 2022/12

Y1 - 2022/12

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AB - 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 Å resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development.

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Molecular basis for inhibiting human glucose transporters by exofacial inhibitors

Abstract

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