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

作者：Vashisth Harish^*; Abrams Cameron F

来源：Journal of Molecular Biology, 2010, 400(3): 645-658.

DOI：10.1016/j.jmb.2010.05.025

• molecular dynamics
• Monte Carlo docking
• ligand/receptor interactions
• homology model
• conformational flexibility

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 IGF1R Delta beta, we present the first experimentally consistent all-atom structural models of IGF1/IGF1R Delta beta and IGF2/IGF1R Delta beta complexes. Our explicit-solvent molecular dynamics (MD) simulation of apo-IGF1R Delta beta 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 IGF1R Delta beta 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 / IGF1R Delta beta model provides structural bases for the observation that a single IGF1 molecule binds to IGF1R Delta beta 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.

• 出版日期2010-7-16