A novel strategy for understanding how insulin binds to its 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 that 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, removal of carbohydrates from the surface of the receptor greatly increases conformational stability of the molecule, which in turn will increase its ability to crystallise and hence to reveal its structure.
Project Aim: The aim is to design, clone and express a range of deglycosylated insulin and insulin-like growth factor receptor fragments in transient mammalian cell culture systems. The student will test expression levels of these receptor fragments and assess whether they remain functional and properly folded. The best of these will be used to advance our structural studies of the ligand-bound forms of these receptors, with the view to revealing 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
- 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.
- Elleman TC, Frenkel MJ, Hoyne PA, McKern NM, et al. Mutational analysis of the N-linked glycosylation sites of the human insulin receptor. Biochem J. 2000 347:771-9.
- Sparrow LG, Lawrence MC, Gorman JJ, Strike PM, et al. N-linked glycans of the human insulin receptor and their distribution over the crystal structure. Proteins: Struct Funct Bioinform. 2007 71:426-39.
Research interests
In healthy individuals, the insulin and type 1 insulin-like growth factor receptor mediate the signalling events associated with glucose homeostasis and normal cell growth. However, aberrant signalling associated with thiese receptors 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
- 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.
- 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
cancer, insulin, insulin-like growth factors, receptors