Related Experiment Video

Updated: Aug 27, 2025

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion
07:30

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion

Published on: May 10, 2018

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Activation of the human insulin receptor by non-insulin-related peptides

Nicholas S Kirk1,2, Qi Chen3, Yingzhe Ginger Wu3

  • 1WEHI, 1G Royal Parade, Parkville, VIC, 3052, Australia.

Nature Communications
|September 28, 2022
PubMed

Insights

Researchers discovered a novel 33-mer polypeptide that activates the human insulin receptor. This non-insulin molecule mimics insulin signaling pathways, offering new therapeutic development opportunities for insulin mimetics.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • The insulin receptor (IR) is crucial for glucose homeostasis.
  • Insulin binding induces conformational changes in the IR, activating intracellular signaling.
  • Understanding alternative activation mechanisms is key for therapeutic development.

Purpose of the Study:

  • To investigate if non-insulin molecules can activate the insulin receptor.
  • To elucidate the structural basis of activation by an unrelated polypeptide.

Main Methods:

  • Single-particle cryo-electron microscopy (cryo-EM) to determine structural conformations.
  • Analysis of a 33-mer polypeptide's interaction with the insulin receptor.

Main Results:

  • A 33-mer polypeptide, unrelated to insulin, was shown to activate the insulin receptor.
  • The polypeptide binds to two distinct sites on the receptor, inducing a signaling-active conformation.
  • The induced conformation differs from, yet relates to, insulin-bound states.

Conclusions:

  • Identified novel binding motifs on the insulin receptor that can be mimicked by small molecules.
  • Revealed unexplored mechanisms for controlling insulin receptor signaling.
  • Opened new avenues for developing small-molecule insulin mimetics.

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