TY - JOUR
T1 - Molecular basis for inhibiting human glucose transporters by exofacial inhibitors
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
N1 - Funding Information:
We thank Kunio Hirata at Super Photon ring-8 (SPring-8, Japan) BL32XU beamline for the help of crystal screening and data collection. We thank the X-ray Crystallography Platform of the Tsinghua University Technology Center for Protein Research for the crystallization facility. This work was funded by the National Natural Science Foundation of China (SQ2020YFA050052, 31630017, 81861138009, and 31611130036) and Beijing Nova Program (Z201100006820039).
Funding Information:
We thank Kunio Hirata at Super Photon ring-8 (SPring-8, Japan) BL32XU beamline for the help of crystal screening and data collection. We thank the X-ray Crystallography Platform of the Tsinghua University Technology Center for Protein Research for the crystallization facility. This work was funded by the National Natural Science Foundation of China (SQ2020YFA050052, 31630017, 81861138009, and 31611130036) and Beijing Nova Program (Z201100006820039).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85130021079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130021079&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-30326-3
DO - 10.1038/s41467-022-30326-3
M3 - Article
C2 - 35552392
AN - SCOPUS:85130021079
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2632
ER -