Structure and autoregulation of IGF-1 receptor tyrosine kinase
We are studying the structure and function of the insulin-like growth factor 1 receptor (IGF1R). Like insulin receptor, IGF1R contains two extracellular ligand binding a-subunits and two transmembrane b-subunits. The b-subunits possess tyrosine kinase catalytic domains that are activated upon ligand binding.
Using the purified tyrosine kinase domain, we found that IGF1R is regulated by intermolecular autophosphorylation at 3 tyrosine residues. By steady-state kinetic analyses of the isolated phosphorylated forms of IGF1R, we determined that each autophosphorylation promotes substrate binding and increases the catalytic efficiency of IGF1R. In collaboration with Dr. Stevan Hubbard of NYU Medical School, we crystallized the IGF1R kinase domain in a complex with a peptide substrate and an ATP analog, and determined its three-dimensional structure.
|The structure of the IGF1R kinase domain. Secondary structural elements of IGF1R are shaded blue (b-sheets) and red (a-helices). The ATP analog is in black, and the peptide substrate (derived from the sequence of IRS-1) is shown in yellow.|
|IGF1R has emerged as an important target for anti-cancer drug design. A recent goal of our laboratory is to use the biochemical and structural information to develop conformation-selective inhibitors of IGF1R.|
For more details on this work, see:
S. Favelyukis, J.H. Till, S.R. Hubbard, and W.T. Miller (2001). Nature Structural Biology 8 ,1058-1063.
M. Amoui, B.P. Craddock, and W.T. Miller (2001). Differential phosphorylation of IRS-1 by insulin and insulin-like growth factor 1 receptors in Chinese hamster ovary cells. J. Endocrinology 171, 153-162.
W. Li, S. Favelyukis, J. Yang, Y. Zeng, J. Yu, A. Gangjee, and W.T. Miller (2004). Inhibition of insulin-like growth factor I receptor autophosphorylation by novel 6-5 ring-fused compounds. Biochem. Pharm 68, 145-154.
W. Li and W.T. Miller (2006). Role of the activation loop tyrosines in regulation of the insulin-like growth factor I receptor tyrosine kinase. J. Biol. Chem 281, 23785-23791.
J. Wu, W. Li, B.P. Craddock, K.W. Foreman, M.J. Mulvihill, Q.Ji, W.T. Miller, and S.R. Hubbard (2008). Small-molecule inhibition and activation loop trans-autophosphorylation of the IGF1 receptor. EMBO Journal. 27, 1985-1994.
B.P. Craddock and W.T. Miller (2012). Effects of somatic mutations in the C-terminus of IGF1R on activity and signaling. J. Signal Trans. 804801.