Associate Professor Mike Lawrence
Division: Structural Biology
The insulin receptor (IR) and the type-1 insulin-like growth factor receptor (IGF-1R) are closely related members of the receptor tyrosine kinase superfamily. IR is the receptor through which insulin exerts its actions. These are the regulation of lipid, protein and carbohydrate metabolism including the maintenance of glucose homeostasis. The IGF-1R is involved in normal growth and development and there is a compelling body of evidence for involvement of the IGF signalling system in cancer progression.
Dr Mike Lawrence and Dr Colin Ward are interested in understanding the way in which insulin and the IGFs bind to these receptors on the surface of cells. Their work has led to the first structure of the intact extra-cellular part of the insulin receptor and has shown for the first time the way in which the insulin binding site is constructed. The challenge is now to find out exactly how insulin binds to this site and to understand how the ligand-binding signal is transmitted across the cell membrane.
Since aberrant signalling by IGF-2 binding to IR and IGF-1 and IGF-2 binding to IGF-1R has been shown to play a role in the development and progression of cancer and we are also seeking to understand ligand binding to IGF-1R.
- Smith BJ, Huang K, Kong G, Chan SJ, Nakagawa S, Menting JG, Hu SQ, Whittaker J, Steiner DF, Katsoyannis PG, Ward CW, Weiss MA, Lawrence MC. Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists Proc Natl Acad Sci U S A 2010 Apr 13; 107 (15) 6771-6776. PMID: 20348418 [PubMed - in process]
- Whitten AE, Smith BJ, Menting JG, Margetts MB, McKern NM, Lovrecz GO, Adams TE, Richards K, Bentley JD, Trewhella J, Ward CW, Lawrence MC. Solution structure of ectodomains of the insulin receptor family: the ectodomain of the type 1 insulin-like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change. Journal of Molecular Biology, 2009, Dec 18; 394(5), 878-892. PMID: 19835884 [PubMed - indexed for MEDLINE]
- 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 Mar 9;31(4):422-434. PMID: 19274663 [PubMed - indexed for MEDLINE]
- Sparrow LG, Lawrence MC, Gorman JJ, Strike PM, Robinson CP, McKern NM, Ward CW. N-linked glycans of the human insulin receptor and their distribution over the crystal structure. Proteins. 2008 Apr;71(1):426-39. PMID: 17957771 [PubMed - indexed for MEDLINE]
- Lawrence MC, McKern NM, Ward CW. Insulin receptor structure and its implications for the IGF-1 receptor. Curr Opin Struct Biol. 2007 Dec;17(6):699-705. Review. PMID: 17851071 [PubMed - indexed for MEDLINE]
- Zahnd C, Wyler E, Schwenk JM, Steiner D, Lawrence MC, McKern NM, Pecorari F, Ward CW, Joos TO, Plückthun A. A designed ankyrin repeat protein evolved to picomolar affinity to Her2. J Mol Biol. 2007 Jun 15;369(4):1015-28 PMID: 17466328 [PubMed - indexed for MEDLINE]
- Ward CW, Lawrence MC, Streltsov VA, Adams TE, McKern NM. The insulin and EGF receptor structures: new insights into ligand-induced receptor activation. Trends Biochem Sci. 2007 Mar;32(3):129-37 PMID: 17280834 [PubMed - indexed for MEDLINE]
- McKern NM, Lawrence MC, Streltsov VA, Lou MZ, Adams TE, Lovrecz GO, Elleman TC, Richards KM, Bentley JD, Pilling PA, Hoyne PA, Cartledge KA, Pham TM, Lewis JL, Sankovich SE, Stoichevska V, Da Silva E, Robinson CP, Frenkel MJ, Sparrow LG, Fernley RT, Epa VC, Ward CW. Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature. 2006 Sep 14;443(7108):218-21 PMID: 16957736 [PubMed - indexed for MEDLINE]
- Carmichael JA, Lawrence MC, Graham LD, Pilling PA, Epa VC, Noyce L, Lovrecz G, Winkler DA, Pawlak-Skrzecz A, Eaton RE, Hannan GN, Hill RJ. The X-ray structure of a hemipteran ecdysone receptor ligand-binding domain: comparison with a lepidopteran ecdysone receptor ligand-binding domain and implications for insecticide design. J Biol Chem. 2005 Jun 10;280(23):22258-69 PMID: 15809296 [PubMed - indexed for MEDLINE]
- Lawrence MC, Borg NA, Streltsov VA, Pilling PA, Epa VC, Varghese JN, McKimm-Breschkin JL, Colman PM. Structure of the haemagglutinin-neuraminidase from human parainfluenza virus type III. J Mol Biol. 2004 Jan 30;335(5):1343-57 PMID: 14729348 [PubMed - indexed for MEDLINE]
Current Laboratory Members
Faculty Member: Michael Lawrence, BSc(Hons) PhD Cape Town
Faculty Member: Colin Ward, BSc(Hons) PhD UNSW
Senior Research Assistant: John Menting, BSc(Hons) Melb PhD LaT
Post-Doctoral Fellow: Geoffrey Kong, BSc(Hons) Melb PhD Melb
Research Assistant: Mai Margetts, BAppSc RMIT