Paper Citing NAMD - Abstract
Vashisth, Harish; Abrams, Cameron F.
All-Atom Structural Models for Complexes of Insulin-Like Growth Factors IGF1 and IGF2 with Their Cognate Receptor
JOURNAL OF MOLECULAR BIOLOGY, 400:645-658, JUL 16 2010
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. (C) 2010 Elsevier Ltd. All rights reserved.
