A model for insulin binding to the insulin receptor

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Insulin receptor binding is crucial for glucose homeostasis.
• Classical binding sites and negative cooperativity are known phenomena.
• Insulin analogues offer tools to probe receptor interactions.

Purpose of the Study:

• To investigate the binding properties of insulin analogues to insulin receptors.
• To identify novel receptor binding domains on insulin molecules.
• To propose a molecular model for insulin receptor binding and negative cooperativity.

Main Methods:

• Determining binding affinities of insulin analogues to human insulin receptor (hIR), truncated soluble hIR, and human insulin-like growth factor 1 receptor (hIGF-1R).
• Analyzing binding data to identify anomalous properties associated with specific insulin analogue substitutions.
• Developing a molecular model based on experimental observations.

Main Results:

• Insulin analogues with substitutions at A13 or B17 positions exhibited anomalous binding.
• These positions, on the hexamer-forming surface, suggest a second receptor binding domain.
• A model was proposed where two alpha subunits of the insulin receptor form high- and low-affinity binding sites, explaining negative cooperativity.

Conclusions:

• The A13 and B17 positions represent a second important domain for insulin receptor binding.
• A two-site binding model involving both alpha subunits of the insulin receptor explains observed binding phenomena.
• This model provides a molecular basis for negative cooperativity in insulin receptor binding.