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Theoretical and computational studies of peptides and receptors of the insulin family.

Vashisth H - Membranes (Basel) (2015)

Bottom Line: While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments.Particularly, applications of molecular dynamics (MD) and Monte Carlo (MC) simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains.The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of New Hampshire, 33 Academic Way, Durham, NH 03824, USA. Harish.Vashisth@unh.edu.

ABSTRACT
Synergistic interactions among peptides and receptors of the insulin family are required for glucose homeostasis, normal cellular growth and development, proliferation, differentiation and other metabolic processes. The peptides of the insulin family are disulfide-linked single or dual-chain proteins, while receptors are ligand-activated transmembrane glycoproteins of the receptor tyrosine kinase (RTK) superfamily. Binding of ligands to the extracellular domains of receptors is known to initiate signaling via activation of intracellular kinase domains. While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments. Here, we review how this useful structural information (on ligands and receptors) has enabled large-scale atomically-resolved simulations to elucidate the conformational dynamics of these biomolecules. Particularly, applications of molecular dynamics (MD) and Monte Carlo (MC) simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains. The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

No MeSH data available.


Related in: MedlinePlus

Three allosteric forms of insulin hexamers. T6, T3R3 and R6 insulin hexamers are shown in cartoon representations. The color scheme for the insulin monomers is the same as in Figure 1. Additionally, six zinc-coordinating histidine residues from six B chains (cyan) and six phenols (magenta; R6 only) are shown in stick representations. Disulfide bonds are omitted for clarity. Approximate locations of two key interfaces (dimer and hexamer-forming) are also marked (left).
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f2-membranes-05-00048: Three allosteric forms of insulin hexamers. T6, T3R3 and R6 insulin hexamers are shown in cartoon representations. The color scheme for the insulin monomers is the same as in Figure 1. Additionally, six zinc-coordinating histidine residues from six B chains (cyan) and six phenols (magenta; R6 only) are shown in stick representations. Disulfide bonds are omitted for clarity. Approximate locations of two key interfaces (dimer and hexamer-forming) are also marked (left).

Mentions: The unique features present in the N- and C-termini of the insulin B-chain allow the hormone to dimerize or hexamerize (in the presence of zinc or phenol) via self-assembly. Such insulin hexamers can exist in a dynamic equilibrium between three allosteric states, known as T6,T3R3 and R6 [28,29,30,31,32,33,34,35,36,37], that can be shifted to R6 only by phenolic species [102,103,104]. However, one can achieve the T3R3 state by phenolic species or concentrated anionic medium or both. Six hydrophobic pockets exist for phenolic ligands in R6 hexamers, but not in T6 hexamers. The overall arrangement of insulin monomers in three hexameric allosteric states is shown in Figure 2. No structural evidence exists for the oligomerization or conformational change in IGFs, but it has been suggested that the N-terminus of IGF1 may undergo a conformational change that affects its receptor binding affinity [105].


Theoretical and computational studies of peptides and receptors of the insulin family.

Vashisth H - Membranes (Basel) (2015)

Three allosteric forms of insulin hexamers. T6, T3R3 and R6 insulin hexamers are shown in cartoon representations. The color scheme for the insulin monomers is the same as in Figure 1. Additionally, six zinc-coordinating histidine residues from six B chains (cyan) and six phenols (magenta; R6 only) are shown in stick representations. Disulfide bonds are omitted for clarity. Approximate locations of two key interfaces (dimer and hexamer-forming) are also marked (left).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384091&req=5

f2-membranes-05-00048: Three allosteric forms of insulin hexamers. T6, T3R3 and R6 insulin hexamers are shown in cartoon representations. The color scheme for the insulin monomers is the same as in Figure 1. Additionally, six zinc-coordinating histidine residues from six B chains (cyan) and six phenols (magenta; R6 only) are shown in stick representations. Disulfide bonds are omitted for clarity. Approximate locations of two key interfaces (dimer and hexamer-forming) are also marked (left).
Mentions: The unique features present in the N- and C-termini of the insulin B-chain allow the hormone to dimerize or hexamerize (in the presence of zinc or phenol) via self-assembly. Such insulin hexamers can exist in a dynamic equilibrium between three allosteric states, known as T6,T3R3 and R6 [28,29,30,31,32,33,34,35,36,37], that can be shifted to R6 only by phenolic species [102,103,104]. However, one can achieve the T3R3 state by phenolic species or concentrated anionic medium or both. Six hydrophobic pockets exist for phenolic ligands in R6 hexamers, but not in T6 hexamers. The overall arrangement of insulin monomers in three hexameric allosteric states is shown in Figure 2. No structural evidence exists for the oligomerization or conformational change in IGFs, but it has been suggested that the N-terminus of IGF1 may undergo a conformational change that affects its receptor binding affinity [105].

Bottom Line: While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments.Particularly, applications of molecular dynamics (MD) and Monte Carlo (MC) simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains.The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of New Hampshire, 33 Academic Way, Durham, NH 03824, USA. Harish.Vashisth@unh.edu.

ABSTRACT
Synergistic interactions among peptides and receptors of the insulin family are required for glucose homeostasis, normal cellular growth and development, proliferation, differentiation and other metabolic processes. The peptides of the insulin family are disulfide-linked single or dual-chain proteins, while receptors are ligand-activated transmembrane glycoproteins of the receptor tyrosine kinase (RTK) superfamily. Binding of ligands to the extracellular domains of receptors is known to initiate signaling via activation of intracellular kinase domains. While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments. Here, we review how this useful structural information (on ligands and receptors) has enabled large-scale atomically-resolved simulations to elucidate the conformational dynamics of these biomolecules. Particularly, applications of molecular dynamics (MD) and Monte Carlo (MC) simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains. The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

No MeSH data available.


Related in: MedlinePlus