Molecular basis for inhibiting human glucose transporters by exofacial inhibitors.

TitleMolecular basis for inhibiting human glucose transporters by exofacial inhibitors.
Publication TypeJournal Article
Year of Publication2022
AuthorsWang, N, Zhang, S, Yuan, Y, Xu, H, Defossa, E, Matter, H, Besenius, M, Derdau, V, Dreyer, M, Halland, N, He, KHu, Petry, S, Podeschwa, M, Tennagels, N, Jiang, X, Yan, N
JournalNat Commun
Volume13
Issue1
Pagination2632
Date Published2022 05 12
ISSN2041-1723
KeywordsGlucose, Glucose Transport Proteins, Facilitative, Glucose Transporter Type 1, Glucose Transporter Type 3, Humans, Insulin
Abstract

<p>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.</p>

DOI10.1038/s41467-022-30326-3
Alternate JournalNat Commun
PubMed ID35552392
PubMed Central IDPMC9098912
Grant ListSQ2020YFA050052 / / National Natural Science Foundation of China (National Science Foundation of China) /
31630017 / / National Natural Science Foundation of China (National Science Foundation of China) /
81861138009 / / National Natural Science Foundation of China (National Science Foundation of China) /
Z201100006820039 / / Beijing Nova Program /