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Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2

Jiří Jiráček1, Irena Selicharová1, Lenka Žáková1

  • 1From Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic.

Vitamins and Hormones
|September 17, 2023
PubMed

Insights

Understanding how insulin and related growth factors bind to receptors is key. Recent cryo-EM structures, combined with hormone mutagenesis, reveal insights into these crucial molecular interactions.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Endocrinology

Background:

  • Insulin and insulin-like growth factors (IGF-1, IGF-2) regulate cellular functions by binding to their receptors (IR, IGF-1R).
  • Determining the 3D structure of these hormone-receptor complexes is challenging due to receptor flexibility and dynamic hormone interactions.
  • Previous studies utilized hormone mutagenesis and kinetic analyses to probe receptor binding sites.

Purpose of the Study:

  • To investigate the binding mechanisms of insulin, IGF-1, and IGF-2 to their respective receptors.
  • To elucidate the role of specific hormone binding sites, particularly site 2, in receptor activation.
  • To integrate structure-activity relationship data with recent cryo-electron microscopy (cryoEM) findings.

Main Methods:

  • Detailed mutagenesis of insulin, IGF-1, and IGF-2, focusing on modifications to hypothetical binding site 2.
  • Structure-activity relationship (SAR) studies to assess the impact of mutations on hormone function.
  • Analysis of experimental data in the context of recently published cryoEM structures of hormone-receptor complexes.

Main Results:

  • Mutagenesis studies provided critical data on the contribution of hormone binding site 2 to receptor interaction.
  • Structure-activity relationships revealed how modifications affect hormone binding and receptor activation.
  • Recent cryoEM structures offer unprecedented atomic-level detail of hormone-receptor complexes.

Conclusions:

  • The combination of mutagenesis and cryoEM structural data significantly advances the understanding of insulin and IGF signaling.
  • Hypothetical binding site 2 plays a crucial role in the interaction of insulin and IGFs with their receptors.
  • This integrated approach provides a foundation for future research into receptor activation and therapeutic target identification.
Keywords:
Binding siteHormone analogIGF-1IGF-2InsulinInsulin receptorMutagenesisStructure

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