Gill, R. and Verma, C. and Wallach, B. and Urs, B. and Pitts, James and Wollmer, A. and De Meyts, P. and Wood, S.P. (1999) Modelling of the disulphide-swapped isomer of human insulin-like growth factor-1: implications for receptor binding. Protein Engineering, Design and Selection 12 (4), pp. 297-303. ISSN 0269-2139.
Abstract
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 ~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 ~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 α-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 α-helix has uncoiled and this may be hindering interaction of Val44 with the second insulin receptor binding pocket.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Depositing User: | Sarah Hall |
| Date Deposited: | 14 May 2019 09:10 |
| Last Modified: | 02 Aug 2023 17:51 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/27514 |
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