Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks
Open Access
- 8 April 2003
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 100 (8), 4435-4439
- https://doi.org/10.1073/pnas.0830026100
Abstract
Insulin is thought to elicit its effects by crosslinking the two extracellular α-subunits of its receptor, thereby inducing a conformational change in the receptor, which activates the intracellular tyrosine kinase signaling cascade. Previously we identified a series of peptides binding to two discrete hotspots on the insulin receptor. Here we show that covalent linkage of such peptides into homodimers or heterodimers results in insulin agonists or antagonists, depending on how the peptides are linked. An optimized agonist has been shown, both in vitro and in vivo, to have a potency close to that of insulin itself. The ability to construct such peptide derivatives may offer a path for developing agonists or antagonists for treatment of a wide variety of diseases.Keywords
This publication has 13 references indexed in Scilit:
- Peptides Identify the Critical Hotspots Involved in the Biological Activation of the Insulin ReceptorJournal of Biological Chemistry, 2002
- Crystal structure of the first three domains of the type-1 insulin-like growth factor receptorNature, 1998
- Crystal structure of the tyrosine kinase domain of the human insulin receptorNature, 1994
- The structural basis of insulin and insulin-like growth factor-I receptor binding and negative co-operativity, and its relevance to mitogenic versus metabolic signallingDiabetologia, 1994
- A model for insulin binding to the insulin receptorEuropean Journal of Biochemistry, 1994
- Facile synthesis of homogeneous artificial proteinsJournal of the American Chemical Society, 1994
- Concanavalin A-induced receptor aggregation stimulates the tyrosine kinase activity of the insulin receptor in intact cellsBiochemical Journal, 1990
- Monoclonal antibodies to the insulin receptor mimic metabolic effects of insulin but do not stimulate receptor autophosphorylation in transfected NIH 3T3 fibroblasts.Proceedings of the National Academy of Sciences of the United States of America, 1989
- Polylysine specifically activates the insulin-dependent insulin receptor protein kinaseJournal of Biological Chemistry, 1989
- A Simple Free Fat Cell Bioassay for InsulinHormone and Metabolic Research, 1974