All-Atom Structural Models for Complexes of Insulin-Like Growth Factors IGF1 and IGF2 with Their Cognate Receptor

Department of Chemical and Biological Engineering, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.
Journal of Molecular Biology (Impact Factor: 4.33). 07/2010; 400(3):645-58. DOI: 10.1016/j.jmb.2010.05.025
Source: PubMed


Type 1 insulin-like growth factor receptor (IGF1R) is a membrane-spanning glycoprotein of the insulin receptor family that has been implicated in a variety of cancers. The key questions related to molecular mechanisms governing ligand recognition by IGF1R remain unanswered, partly due to the lack of testable structural models of apo or ligand-bound receptor complexes. Using a homology model of the IGF1R ectodomain IGF1RDeltabeta, we present the first experimentally consistent all-atom structural models of IGF1/IGF1RDeltabeta and IGF2/IGF1RDeltabeta complexes. Our explicit-solvent molecular dynamics (MD) simulation of apo-IGF1RDeltabeta shows that it displays asymmetric flexibility mechanisms that result in one of two binding pockets accessible to growth factors IGF1 and IGF2, as demonstrated via an MD-assisted Monte Carlo docking procedure. Our MD-generated ensemble of structures of apo and IGF1-bound IGF1RDeltabeta agrees reasonably well with published small-angle X-ray scattering data. We observe simultaneous contacts of each growth factor with sites 1 and 2 of IGF1R, suggesting cross-linking of receptor subunits. Our models provide direct evidence in favor of suggested electrostatic complementarity between the C-domain (IGF1) and the cysteine-rich domain (IGF1R). Our IGF1/IGF1RDeltabeta model provides structural bases for the observation that a single IGF1 molecule binds to IGF1RDeltabeta at low concentrations in small-angle X-ray scattering studies. We also suggest new possible structural bases for differences in the affinities of insulin, IGF1, and IGF2 for their noncognate receptors.

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    • "Although IGF1 and IGF2 share similarity in structure to insulin (Rinderknecht and Humbel 1976), they bind distinct receptors. Insulin, IGF1 and IGF2 bind the insulin receptor, IGF1 receptor (IGF1R) and IGF2 receptor (IGF2R), respectively (Vashisth and Abrams 2010; Hawkes and Kar 2004). "
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    • "The homology modeling approach is a valuable tool for investigating protein structures when experimental structures are lacking. Homology models are useful for predicting ligand potency and specificity through the use of different docking approaches, and high-quality homology models have also been used in the study of conformational changes using MD simulations [38]. In the present study, 5-HT and ten other tryptamine derivatives (SERT substrates) and the SSRI (S)-citalopram were docked into the putative substrate binding site of a SERT homology model, and possible conformational changes of SERT upon ligand binding were studied by MD simulations. "
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