Insulin plays a crucial physiological role in glucose control by initiating a number of signaling events on binding and activating its cell surface receptor. Insulin mimics have, therefore, become promising agents for treating diabetes and to probe the mechanism of interaction of insulin with its receptor. Specifically, many insulin‐mimetic peptide sequences have been discovered and found to selectively function as agonists and antagonists, but their structures and the mechanistic details of their interactions with the receptor remain challenging to characterize. In this work, we have studied the folding properties and structure of a Site 1 insulin mimetic peptide S371 that has sequence similarities with the insulin B‐chain as well as with a critical hormone‐binding element of the receptor known as the C‐terminal (CT) peptide. We first validated our simulation approaches by predicting the known solution structure of the insulin B‐chain helix and then applied them to study the folding of the mimetic peptide S371. Our data predict a helical fold for the first 16 residues of S371 that has a resemblance to the helical motifs in the insulin B‐chain and CT. We also propose receptor‐bound models of S371 that provide mechanistic explanations for competing binding properties of S371 and CT to the Site 1 of IR. © 2017 Wiley Periodicals, Inc.
The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.
more » « less- NSF-PAR ID:
- 10000991
- Publisher / Repository:
- eLife Sciences Publications, Ltd.
- Date Published:
- Journal Name:
- eLife
- Volume:
- 3
- ISSN:
- 2050-084X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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LINKED ARTICLES This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit
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