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Hubbard Lab Research Insulin Receptor

Insulin Receptor

Using X-ray crystallography as our primary experimental technique, researchers in the Hubbard Lab are attempting to understand the molecular basis for insulin receptor activation and for recruitment of downstream signaling proteins to the activated (phosphorylated) insulin receptor (see figure 1).

Several cytoplasmic adapter proteins bind to the activated insulin receptor, including insulin receptor substrate (IRS) proteins and APS, which are positive factors in insulin signaling pathways culminating in glucose uptake. The insulin receptor is downregulated by the adapter proteins Grb14 and Grb10 as well as the tyrosine phosphatase PTP1B.

Model of the Interaction Between Grb14 and the Activated Insulin Receptor
Figure 1: Model of the interaction between Grb14 and the activated insulin receptor.

Read more in our paper “Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14” published in Nature Structural & Molecular Biology.

We are determining crystal structures of complexes between these proteins and the insulin receptor kinase domain to elucidate the modes of interaction and the determinants of specificity (see figure 2).

Model of the KRLB Region of IRS2 Bound to Tri-Phosphorylated IRK
Figure 2: The KRLB region of IRS2 bound to tri-phosphorylated IRK. The N-terminal kinase lobe is colored dark gray, the C-terminal lobe is colored light gray, and the KRLB region (residues 620–634) is shown in stick representation. Atoms of the activation loop and catalytic loop of IRK are colored green and orange, respectively.

Read more in our paper “Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2” published in Nature Structural & Molecular Biology.