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Extracellular Glucose Depletion as an Indirect Measure of Glucose Uptake in Cells and Tissues Ex Vivo
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Molecular basis for inhibiting human glucose transporters by exofacial inhibitors

Nan Wang1, Shuo Zhang1, Yafei Yuan1

  • 1State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.

Nature Communications
|May 13, 2022
PubMed

Insights

Researchers engineered a GLUT3 variant to discover exofacial inhibitors. They identified SA47, a novel GLUT3 inhibitor, and determined its binding structure, paving the way for new cancer and diabetes therapies.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Drug Discovery

Background:

  • Human glucose transporters (GLUTs) facilitate hexose uptake, with elevated GLUT1 and GLUT3 expression fueling cancer cell hyperproliferation.
  • GLUT inhibitors are investigated as anticancer therapeutics, and GLUT inhibitor-conjugated insulin is explored for type 1 diabetes management.

Purpose of the Study:

  • To engineer a GLUT3 variant (GLUT3exo) for screening exofacial GLUT1/3 inhibitors.
  • To identify and characterize novel exofacial GLUT3 inhibitors for therapeutic applications.

Main Methods:

  • Engineering of a GLUT3 variant (GLUT3exo) for exofacial inhibitor screening.
  • Identification of an exofacial GLUT3 inhibitor, SA47.
  • Elucidation of SA47's mode of action via 2.3 Å resolution crystal structure of SA47-bound GLUT3.

Main Results:

  • Successful engineering of GLUT3exo for exofacial inhibitor screening.
  • Identification and structural characterization of SA47 as a novel exofacial GLUT3 inhibitor.
  • Determination of the binding mode of SA47 to GLUT3.

Conclusions:

  • The engineered GLUT3exo serves as a platform for discovering exofacial GLUT inhibitors.
  • SA47 represents a promising lead compound for developing therapeutics targeting GLUTs.
  • This work provides a framework for advancing exofacial GLUT inhibitor discovery for cancer and diabetes treatments.

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