Molecular basis for inhibiting human glucose transporters by exofacial inhibitors

Autor:	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
Rok vydání:	2021
Předmět:	Glucose Transporter Type 1 Multidisciplinary Glucose Glucose Transporter Type 3 Glucose Transport Proteins Facilitative General Physics and Astronomy Humans Insulin General Chemistry General Biochemistry Genetics and Molecular Biology
Zdroj:	Nature communications. 13(1)
ISSN:	2041-1723
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13cf0f8ec33788632d037a0b888d3098 https://pubmed.ncbi.nlm.nih.gov/35552392 Zobrazit plný text záznamu Full text from SpringerLink