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

    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.

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    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.


    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


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