Ligand binding to the insulin-like growth factor receptor
Project type
Honours
| Supervisor(s) | Division | |
| (Primary) | Structural Biology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Structural Biology | .(JavaScript must be enabled to view this email address) |
Details of project
Project Background: Our laboratory is interested in understanding how insulin and insulin-like growth factors bind to their receptors. These systems are highly related, but surprisingly little is known about the structural detail of these events, despite their considerable interest in the disease states of diabetes and cancer.
Project Rationale: One of the reasons for this shortage of information is the fact that there are intrinsic instabilities within the ligand/receptor complex itself, which impacts on its ability to crystallise and hence its success in structural studies. We have recently discovered a number of strategies that can be used to overcome these difficulties and we are in the process of testing these. In particular, our recent findings show that it is indeed possible to make enzymatically-modified insulin that binds insulin receptor with approximately two orders of magnitude higher affinity than native hormone and which adds considerable stability to the ligand/receptor complex.
Project Aim: The aim is to extend the above findings and make enzymatically-modified insulin-like growth factors. These compounds have the potential to advance significantly our structural studies of how insulin-like growth factors bind to the Type 1 insulin-like growth factor receptor and hence have the potential to reveal new strategies in targeting these receptors in cancer.
The Student: The student will be expected to have a keen interest in proteins and in the application of structural biology to advancing anti-cancer therapy.
Project references
- Smith BJ, Huang K, Kong G, Chan SJ, et al.: Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists. Proc Natl Acad Sci USA. 2010 107:6771-6.
- Lawrence MC, McKern NM, Ward CW: Insulin receptor structure and its implications for the IGF-1 receptor. Curr Opin Struct Biol. 2007 17:699-705.
- Menting JG, Ward CW, Margetts MB, Lawrence MC: A thermodynamic study of ligand binding to the first three domains of the human insulin receptor: relationship between the receptor α-chain c-terminal peptide and the site 1 insulin mimetic peptides. Biochemistry. 2009 48:5492-500.
Research interests
In a healthy individual, the insulin and type 1 insulin-like growth factor receptor mediate the signalling events associated with glucose homeostasis and normal cell growth. However, their aberrant signalling plays a role in both cancer development and progression.
Surprisingly, no atomic level information exists of the way these receptors bind ligand and transfer signal. We are seeking to obtain three-dimensional structures of these receptors in complex with ligand and to understand the signalling mechanism. Insights from our structure of the unliganded insulin receptor ectodomain are now being exploited to achieve these goals, with the potential to open up new therapeutic opportunities for cancer as well as diabetes.
Selected publications
- McKern NM, Lawrence MC, Streltsov VA, Lou MZ, et al. Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature. 2006 443:218-21.
- Lawrence MC, McKern NM, Ward CW: Insulin receptor structure and its implications for the IGF-1 receptor. Curr Opin Struct Biol. 2007 17:699-705.
- Ward CW, Lawrence MC: Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor. Bioessays. 2009 31:422-34.
Research theme
Cancer
Scientific discipline
- Structural Biology
Keywords
insulin-like growth factors, cancer, diabetes, receptors