Modelling of the disulphide-swapped isomer of human insulin-like growth factor-1: implications for receptor binding

Raj Gill, Chandra Verma, Brenda Wallach, Birgitte Ursø, Jim Pitts, Axel Wollmer, Pierre De Meyts, Steve Wood*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Insulin-like growth factor-1 (IGF-1) is a serum protein which unexpectedly folds to yield two stable tertiary structures with different disulphide connectivities; native IGF-1 [18-61,6-48,47-52] and IGF-1 swap [18-61,6-47, 48-52]. Here we demonstrate in detail the biological properties of recombinant human native IGF-1 and IGF-1 swap secreted from Saccharomyces cerevisiae. IGF-1 swap had a approximately 30 fold loss in affinity for the IGF-1 receptor overexpressed on BHK cells compared with native IGF-1. The parallel increase in dose required to induce negative cooperativity together with the parallel loss in mitogenicity in NIH 3T3 cells implies that disruption of the IGF-1 receptor binding interaction rather than restriction of a post-binding conformational change is responsible for the reduction in biological activity of IGF-1 swap. Interestingly, the affinity of IGF-1 swap for the insulin receptor was approximately 200 fold lower than that of native IGF-1 indicating that the binding surface complementary to the insulin receptor (or the ability to attain it) is disturbed to a greater extent than that to the IGF-1 receptor. A 1.0 ns high-temperature molecular dynamics study of the local energy landscape of IGF-1 swap resulted in uncoiling of the first A-region alpha-helix and a rearrangement in the relative orientation of the A- and B-regions. The model of IGF-1 swap is structurally homologous to the NMR structure of insulin swap and CD spectra consistent with the model are presented. However, in the model of IGF-1 swap the C-region has filled the space where the first A-region alpha-helix has uncoiled and this may be hindering interaction of Val44 with the second insulin receptor binding pocket.

Original languageEnglish
Pages (from-to)297-303
Number of pages7
JournalProtein Engineering
Issue number4
Publication statusPublished - Apr 1999


  • 3T3 Cells
  • Adipocytes
  • Animals
  • Chromatography
  • Circular Dichroism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Insulin/chemistry
  • Insulin-Like Growth Factor I/chemistry
  • Isomerism
  • Mice
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Rats
  • Saccharomyces cerevisiae/chemistry
  • Structure-Activity Relationship
  • Thymidine/metabolism
  • Time Factors


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