Insulin mimetic peptide disrupts the primary binding site of the insulin receptor
Publication Year 2016-06-08,Volume 291,Issue #30,Page 15473-15481
Journal Title
Journal of Biological Chemistry
Publication Type
Journal Article
Sets of synthetic peptides that interact with the insulin receptor ectodomain have been discovered by phage display and reported in the literature. These peptides were grouped into three classes termed Site 1, Site 2 and Site 3 based on their mutual competition of binding to the receptor. Further refinement has yielded, in particular, a 36-residue Site 2 / Site 1 fusion peptide S519 which binds the insulin receptor with sub-nanomolar affinity and exhibits agonist activity in both lipogenesis and glucose uptake assays. Here, we report three-dimensional crystallographic detail of the interaction of the C-terminal, 16-residue Site 1 component (S519C16) of S519 with the first leucine-rich repeat domain (L1) of the insulin receptor. Our structure shows that S519C16 binds to the same site on the L1 surface as that occupied by a critical component of the primary binding site, namely, the helical C-terminal segment of the insulin receptor alpha-chain (termed alphaCT). In particular, the two phenylalanine residues within the FYXWF motif of S519C16 are seen to engage the insulin receptor L1 domain surface in a fashion almost identical to the respective alphaCT residues Phe701 and Phe705. The structure provides a platform for the further development of peptidic and/or small-molecule agents directed towards the insulin receptor and/or the Type 1 insulin-like growth factor receptor.
WEHI Research Division(s)
Structural Biology
PubMed ID
NHMRC Grants
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Creation Date: 2016-06-16 12:25:10
Last Modified: 2018-07-05 09:18:36
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