Ligand‐induced activation of the insulin receptor: a multi‐step process involving structural changes in both the ligand and the receptor

  title={Ligand‐induced activation of the insulin receptor: a multi‐step process involving structural changes in both the ligand and the receptor},
  author={Colin W. Ward and Michael C. Lawrence},
Current models of insulin binding to the insulin receptor (IR) propose (i) that there are two binding sites on the surface of insulin which engage with two binding sites on the receptor and (ii) that ligand binding involves structural changes in both the ligand and the receptor. Many of the features of insulin binding to its receptor, namely B‐chain helix interactions with the leucine‐rich repeat domain and A‐chain residue interactions with peptide loops from another part of the receptor, are… 

All‐atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone‐binding element

Using various atomistic simulation approaches, all‐atom structural models of hormone/receptor complexes in the presence of CT in its crystallographic position and a thermodynamically favorable displaced position are constructed and suggest that R‐insulin potentially represents the receptor‐bound form of hormone.

The insulin receptor changes conformation in unforeseen ways on ligand binding: Sharpening the picture of insulin receptor activation

The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved.

Elucidating the Activation Mechanism of the Insulin-Family Proteins with Molecular Dynamics Simulations

The simulations have elucidated the crucial differences and similarities in the activation mechanisms of the insulin-family proteins, providing new insights into the molecular mechanisms responsible for the observed differences between IGF-I and IGF-II in receptor binding.

Insulin/receptor binding: The last piece of the puzzle?

A milestone has now been reached with a refined structure of a complex of insulin with a “microreceptor” that contains the primary binding site, and the detailed structure of receptor site 1 is resolved, both without and with insulin.

Structural Dynamics of Insulin Receptor and Transmembrane Signaling.

A critical analysis of the current status of the structure-function relationship of IR is presented, with a comparative assessment of the other IR family receptors, and potential advancements that may provide insight into the molecular mechanism of insulin signaling are discussed.

Theoretical and Computational Studies of Peptides and Receptors of the Insulin Family

Applications of molecular dynamics and Monte Carlo simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains.

Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues

The design and analysis of highly active insulin analogues that are truncated at residue 26 of the B-chain show a structural convergence in the form of a new β-turn at B24-B26 and provide structural details for new approaches in rational design of ligands effective in combating diabetes.

How insulin engages its primary binding site on the insulin receptor

The first view, to the authors' knowledge, of the interaction of insulin with its primary binding site on the insulin receptor is presented, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs, providing an explanation for a wealth of biochemical data from the insulin receptors and IGF1R systems relevant to the design of therapeutic insulin analogues.

All-Atom Structural Models of the Transmembrane Domains of Insulin and Type 1 Insulin-Like Growth Factor Receptors

All-atom structural models of peptides containing 51 residues from the transmembrane and juxtamembrane regions of IR and IGF1R suggest potentially unique structural organization of kinase domains in each receptor.



Structural insights into ligand‐induced activation of the insulin receptor

The structures of the insulin receptor (IR) ectodomain dimer and the L1‐CR‐L2 fragments of IR and insulin‐like growth factor receptor (IGF‐1R) explain many of the features of ligand‐receptor binding and allow the two binding sites on the receptor to be described.

The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity

The crystal structure of the first three domains (L1–CR–L2) of human IR at 2.3 Å resolution is reported and it is shown that the most important differences seen between the two receptors are in the two regions governing ligand specificity.

Alanine Scanning of a Putative Receptor Binding Surface of Insulin-like Growth Factor-I*

The data suggest that IGF-I, in addition to the C-domain, uses surfaces similar to those of insulin in contacting its cognate receptor, although the relative contribution of the side chains of homologous residues varies.

A model for insulin binding to the insulin receptor.

  • L. Schäffer
  • Biology, Chemistry
    European journal of biochemistry
  • 1994
A model is proposed where each of the two alpha subunits of the insulin receptor contributes with a different binding region to the formation of the high-affinity binding site, thus accounting for the curvilinear Scatchard plot.

High-affinity insulin binding: insulin interacts with two receptor ligand binding sites.

Structural-directed alanine scanning mutagenesis is used to identify determinants in these domains involved in ligand interactions of the insulin receptor to demonstrate coexistence of high- and low-affinity binding sites or negative cooperativity.

Insulin receptor structure and its implications for the IGF-1 receptor.

The insulin receptor: a prototype for dimeric, allosteric membrane receptors?

  • P. De Meyts
  • Biology, Chemistry
    Trends in biochemical sciences
  • 2008

Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks

It is shown that covalent linkage of such peptides into homodimer or heterodimers results in insulin agonists or antagonists, depending on how the peptides are linked.