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Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation.

Kiselyov VV, Versteyhe S, Gauguin L, De Meyts P - Mol. Syst. Biol. (2009)

Bottom Line: On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator.Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters.The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs.

View Article: PubMed Central - PubMed

Affiliation: Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark. vkis@novonordisk.com

ABSTRACT
The insulin and insulin-like growth factor 1 receptors activate overlapping signalling pathways that are critical for growth, metabolism, survival and longevity. Their mechanism of ligand binding and activation displays complex allosteric properties, which no mathematical model has been able to account for. Modelling these receptors' binding and activation in terms of interactions between the molecular components is problematical due to many unknown biochemical and structural details. Moreover, substantial combinatorial complexity originating from multivalent ligand binding further complicates the problem. On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator. Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters. The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs.

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Reaction scheme for the insulin receptor binding. (A) Scheme of the crosslinking reaction. (B) Simplified scheme of the insulin receptor kinetic network. S1 and S2 stand for sites 1 and 2, respectively. Insulin is depicted as a black dot.
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f4: Reaction scheme for the insulin receptor binding. (A) Scheme of the crosslinking reaction. (B) Simplified scheme of the insulin receptor kinetic network. S1 and S2 stand for sites 1 and 2, respectively. Insulin is depicted as a black dot.

Mentions: As can be seen from Figure 3B, formation of r1 × 2 from *r1 is rate limited by the first reaction (*r1 → *r1+) with a rate constant, kcr, and dissociation of r1 × 2 into *r1 is also rate limited by the first reaction (r1 × 2 → *r1−), which is a rate constant for dissociation of site 2 in r1 × 2, designated d2′. As the concentration of *r1 is practically the same as that of r1 (approximately 95% of that), the activation scheme shown in Figure 3B can be reduced to a very simple scheme: r1⇄r1 × 2 (see Figure 4A), where the forward reaction has a rate constant equal to kcr, and the reverse—d2′. By analogy, formation of r1 × 2 from r2 is described by a similar scheme: r2⇄r1 × 2 (see Figure 4A), where the rate constant of the reverse reaction (dissociation of site 1 in r1 × 2) is designated as d1′.


Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation.

Kiselyov VV, Versteyhe S, Gauguin L, De Meyts P - Mol. Syst. Biol. (2009)

Reaction scheme for the insulin receptor binding. (A) Scheme of the crosslinking reaction. (B) Simplified scheme of the insulin receptor kinetic network. S1 and S2 stand for sites 1 and 2, respectively. Insulin is depicted as a black dot.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2657531&req=5

f4: Reaction scheme for the insulin receptor binding. (A) Scheme of the crosslinking reaction. (B) Simplified scheme of the insulin receptor kinetic network. S1 and S2 stand for sites 1 and 2, respectively. Insulin is depicted as a black dot.
Mentions: As can be seen from Figure 3B, formation of r1 × 2 from *r1 is rate limited by the first reaction (*r1 → *r1+) with a rate constant, kcr, and dissociation of r1 × 2 into *r1 is also rate limited by the first reaction (r1 × 2 → *r1−), which is a rate constant for dissociation of site 2 in r1 × 2, designated d2′. As the concentration of *r1 is practically the same as that of r1 (approximately 95% of that), the activation scheme shown in Figure 3B can be reduced to a very simple scheme: r1⇄r1 × 2 (see Figure 4A), where the forward reaction has a rate constant equal to kcr, and the reverse—d2′. By analogy, formation of r1 × 2 from r2 is described by a similar scheme: r2⇄r1 × 2 (see Figure 4A), where the rate constant of the reverse reaction (dissociation of site 1 in r1 × 2) is designated as d1′.

Bottom Line: On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator.Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters.The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs.

View Article: PubMed Central - PubMed

Affiliation: Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark. vkis@novonordisk.com

ABSTRACT
The insulin and insulin-like growth factor 1 receptors activate overlapping signalling pathways that are critical for growth, metabolism, survival and longevity. Their mechanism of ligand binding and activation displays complex allosteric properties, which no mathematical model has been able to account for. Modelling these receptors' binding and activation in terms of interactions between the molecular components is problematical due to many unknown biochemical and structural details. Moreover, substantial combinatorial complexity originating from multivalent ligand binding further complicates the problem. On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator. Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters. The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs.

Show MeSH