Journal article
All-Atom Structural Models for Complexes of Insulin-Like Growth Factors IGF1 and IGF2 with Their Cognate Receptor
Journal of molecular biology, v 400(3), pp 645-658
2010
PMID: 20488191
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 IGF1RΔβ, we present the first experimentally consistent all-atom structural models of IGF1/IGF1RΔβ and IGF2/IGF1RΔβ complexes. Our explicit-solvent molecular dynamics (MD) simulation of apo-IGF1RΔβ 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 IGF1RΔβ 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/IGF1RΔβ model provides structural bases for the observation that a single IGF1 molecule binds to IGF1RΔβ 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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Details
- Title
- All-Atom Structural Models for Complexes of Insulin-Like Growth Factors IGF1 and IGF2 with Their Cognate Receptor
- Creators
- Harish VashisthCameron F Abrams
- Publication Details
- Journal of molecular biology, v 400(3), pp 645-658
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000280483100028
- Scopus ID
- 2-s2.0-77954387357
- Other Identifier
- 991014878358704721
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- Web of Science research areas
- Biochemistry & Molecular Biology