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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

Conformational metrics of receptors. (a) Schematic illustration of a side view of the IR ectodomain. The binding pocket (indicated by Rg) is formed by the L1-CR-L2 motif of one subunit (blue) and the F1-F2-F3 motif of the other subunit (red). The L2-F1′ and L1-F2′ interfaces are indicated by vertical lines; line thickness indicates higher/lower buried surface area; (b) Overlay of mapping points on the crystallographic conformation of the IR ectodomain. Each subunit is conceptualized as a linear chain of eight mapping points (indicated by spheres) with an additional mapping point (yellow sphere) joining both subunits at the apex. Each mapping point corresponds to either the center-of-mass of a domain or an interdomain hinge; (c) Hinge angles (F1-F2, L1-L2 and L2-F1) are indicated (top), and the interhinge distances between the L1-L2 and F1-F2 hinge points are also shown (bottom).
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f4-membranes-05-00048: Conformational metrics of receptors. (a) Schematic illustration of a side view of the IR ectodomain. The binding pocket (indicated by Rg) is formed by the L1-CR-L2 motif of one subunit (blue) and the F1-F2-F3 motif of the other subunit (red). The L2-F1′ and L1-F2′ interfaces are indicated by vertical lines; line thickness indicates higher/lower buried surface area; (b) Overlay of mapping points on the crystallographic conformation of the IR ectodomain. Each subunit is conceptualized as a linear chain of eight mapping points (indicated by spheres) with an additional mapping point (yellow sphere) joining both subunits at the apex. Each mapping point corresponds to either the center-of-mass of a domain or an interdomain hinge; (c) Hinge angles (F1-F2, L1-L2 and L2-F1) are indicated (top), and the interhinge distances between the L1-L2 and F1-F2 hinge points are also shown (bottom).

Mentions: The domain organization and structures of receptor ectodomains. (a) A schematic of the domain organization in full-length receptors is shown. The α- and β-chains, as well as receptor domains are labeled. Labels are in the same color as the domains, except insert domains (I), juxtamembrane regions (J), kinase modules (K) and C-terminal tails (C), all of which are depicted by filled patterns; (b,c) Three-dimensional folds of IRΔβ (PDB Code 3LOH) and IGF1RΔβ (homology model of Whitten et al. [73]) are shown with domains of one subunit as space-filling, while identical domains of the other subunit are shown as cartoons. All domains are uniquely colored as in (a). One intersubunit disulfide-bond resolved at Cys524 in IRΔβ and modeled at Cys514 for IGF1RΔβ is shown in green sticks (indicated by green arrows). The αCT peptide is shown only for IRΔβ, as it was resolved [72] after publication of the homology model of IGF1RΔβ [73]. The location of one out of two binding pockets in each receptor ectodomain is marked by an asterisk; see Figure 4a for a side view of this binding pocket.


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

Vashisth H - Membranes (Basel) (2015)

Conformational metrics of receptors. (a) Schematic illustration of a side view of the IR ectodomain. The binding pocket (indicated by Rg) is formed by the L1-CR-L2 motif of one subunit (blue) and the F1-F2-F3 motif of the other subunit (red). The L2-F1′ and L1-F2′ interfaces are indicated by vertical lines; line thickness indicates higher/lower buried surface area; (b) Overlay of mapping points on the crystallographic conformation of the IR ectodomain. Each subunit is conceptualized as a linear chain of eight mapping points (indicated by spheres) with an additional mapping point (yellow sphere) joining both subunits at the apex. Each mapping point corresponds to either the center-of-mass of a domain or an interdomain hinge; (c) Hinge angles (F1-F2, L1-L2 and L2-F1) are indicated (top), and the interhinge distances between the L1-L2 and F1-F2 hinge points are also shown (bottom).
© Copyright Policy
Related In: Results  -  Collection

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

f4-membranes-05-00048: Conformational metrics of receptors. (a) Schematic illustration of a side view of the IR ectodomain. The binding pocket (indicated by Rg) is formed by the L1-CR-L2 motif of one subunit (blue) and the F1-F2-F3 motif of the other subunit (red). The L2-F1′ and L1-F2′ interfaces are indicated by vertical lines; line thickness indicates higher/lower buried surface area; (b) Overlay of mapping points on the crystallographic conformation of the IR ectodomain. Each subunit is conceptualized as a linear chain of eight mapping points (indicated by spheres) with an additional mapping point (yellow sphere) joining both subunits at the apex. Each mapping point corresponds to either the center-of-mass of a domain or an interdomain hinge; (c) Hinge angles (F1-F2, L1-L2 and L2-F1) are indicated (top), and the interhinge distances between the L1-L2 and F1-F2 hinge points are also shown (bottom).
Mentions: The domain organization and structures of receptor ectodomains. (a) A schematic of the domain organization in full-length receptors is shown. The α- and β-chains, as well as receptor domains are labeled. Labels are in the same color as the domains, except insert domains (I), juxtamembrane regions (J), kinase modules (K) and C-terminal tails (C), all of which are depicted by filled patterns; (b,c) Three-dimensional folds of IRΔβ (PDB Code 3LOH) and IGF1RΔβ (homology model of Whitten et al. [73]) are shown with domains of one subunit as space-filling, while identical domains of the other subunit are shown as cartoons. All domains are uniquely colored as in (a). One intersubunit disulfide-bond resolved at Cys524 in IRΔβ and modeled at Cys514 for IGF1RΔβ is shown in green sticks (indicated by green arrows). The αCT peptide is shown only for IRΔβ, as it was resolved [72] after publication of the homology model of IGF1RΔβ [73]. The location of one out of two binding pockets in each receptor ectodomain is marked by an asterisk; see Figure 4a for a side view of this binding pocket.

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