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Insulin and its receptor: structure, function and evolution.
1Receptor Biology Laboratory, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. pdm@novonordisk.com
Summary
Decades of research into insulin-receptor interactions reveal structural insights. A mechanistic model explains insulin binding kinetics and negative cooperativity, despite the complex
Area of Science:
- Structural biology
- Biochemistry
- Molecular interactions
Background:
- The three-dimensional structure of insulin was solved in 1969, detailing self-assembly surfaces.
- Insulin analogues were synthesized to correlate structure with biological function.
- Receptor binding assays and cloning provided tools for structure-function studies.
Purpose of the Study:
- To present a personal perspective on over 30 years of research.
- To develop a mechanistic model for the insulin-receptor interaction.
- To explain the kinetics and negative cooperativity of insulin binding.
Main Methods:
- Analysis of insulin's three-dimensional structure.
- Synthesis and study of hundreds of insulin analogues.
- Utilizing receptor-binding studies and receptor cloning data.
Main Results:
- Understanding of insulin surfaces involved in self-assembly.
- Establishment of structure-function relationships for insulin analogues.
- Assembly of a plausible mechanistic model for insulin-receptor interaction.
Conclusions:
- The developed model explains the kinetics of insulin-receptor binding.
- The model accounts for the phenomenon of negative cooperativity.
- This work integrates diverse data to elucidate a complex molecular interaction.