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Updated: Apr 26, 2026
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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Protective hinge in insulin opens to enable its receptor engagement
John G Menting1, Yanwu Yang2, Shu Jin Chan3
1Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
Summary
Insulin undergoes a conformational change at its B-chain hinge upon receptor binding, enabling key interactions. This structural switch is crucial for insulin function and offers insights for designing new therapeutic analogs.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Endocrinology
Background:
- Insulin's globular structure and receptor binding mechanism are classical yet enigmatic.
- The C-terminal B-chain segment is vital for insulin self-assembly and receptor interaction.
- Understanding insulin's conformational changes is key to its function and therapeutic development.
Purpose of the Study:
- To elucidate the conformational dynamics of insulin upon receptor engagement.
- To investigate the role of the B-chain C-terminal segment in insulin-receptor interaction.
- To provide a structural basis for designing improved insulin analogs.
Main Methods:
- Utilized truncated "microreceptors" to mimic the insulin-binding site.
- Employed nonstandard mutagenesis to probe hinge region function.
- Analyzed conformational changes using structural and functional assays.
Main Results:
- Insulin's B-chain C-terminal segment undergoes a hinge-like rotation upon microreceptor binding.
- This rotation reorients Phe(B24) and positions nonpolar side chains for receptor engagement.
- Mutations disrupting the hinge block receptor binding, while engineered opening affects stability and aggregation.
Conclusions:
- A hinge-opening mechanism facilitates insulin-receptor binding by exposing critical interaction sites.
- This conformational switch reconciles conflicting structural requirements for insulin biosynthesis and function.
- Findings provide a framework for rational design of insulin-based therapeutics.
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