Structure of the insulin receptor ectodomain reveals a folded-over conformation

  title={Structure of the insulin receptor ectodomain reveals a folded-over conformation},
  author={N. M. Mckern and Michael C. Lawrence and Victor A. Streltsov and Meizhen Lou and Timothy E. Adams and George O Lovrecz and Thomas C. Elleman and K M Richards and John D. Bentley and Patricia A. Pilling and Peter A. Hoyne and Kellie Cartledge and Tam M. Pham and Jennifer L. Lewis and Sonia E. Sankovich and Violet Stoichevska and Elizabeth Da Silva and Christine P. Robinson and Maurice J. Frenkel and Lindsay G. Sparrow and Ross T. Fernley and Vidana Chandana Epa and Colin W. Ward},
The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant… 

A Comparative Structural Bioinformatics Analysis of the Insulin Receptor Family Ectodomain Based on Phylogenetic Information

A strong selective pressure was found amongst the IRR orthologous sequences, suggesting that this orphan receptor has a yet unknown physiological role which may be conserved from amphibians to mammals.

Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor

This work presents an all-atom structural model of complex of insulin and the IR ectodomain, where no structural overlap of insulin with the receptor domains (F1 and F2) is observed and suggests ligand cross-linking of receptor subunits.

The signalling conformation of the insulin receptor ectodomain.

The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin’s negative cooperativity of binding likely arises and provides insight into the high affinity of certain super-mitogenic insulins.

Structural and Biological Properties of the Drosophila Insulin-like Peptide 5 Show Evolutionary Conservation*

The crystal structure of two variants of Drosophila melanogaster insulin-like peptide 5 (DILP5) show high evolutionary conservation of the insulin receptor binding properties despite divergent insulin dimerization mechanisms.

The dimeric ectodomain of the alkali-sensing insulin receptor–related receptor (ectoIRR) has a droplike shape

The findings indicate that ectoIRR's sensing of alkaline conditions involves additional molecular mechanisms, for example engagement of receptor juxtamembrane regions or the surrounding lipid environment, which agreed well with previous biochemical and functional analyses of IRR.

Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain

The structural model of the insulin–insulin receptor complex adopts a T-shaped conformation, reveals two additional insulin-binding sites potentially involved in the initial interaction of insulin with its receptor, and resolves the membrane proximal region.

Insulin Mimetic Peptide Disrupts the Primary Binding Site of the Insulin Receptor*

Three-dimensional crystallographic detail of the interaction of the C-terminal, 16-residue Site 1 component (S519C16) of S519 with the first leucine-rich repeat domain (L1) of the insulin receptor is reported.



Three-dimensional Structural Interactions of Insulin and Its Receptor*

The mechanics of a model of receptor activation arising from insulin binding are discussed, and structural details of the interaction of insulin with the receptor that lead to the activation of the intracellular TK are revealed.

Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor

The structure of the first three domains of IGF-1R (L1–Cys-rich–L2) determined to 2.6 Å resolution shows how the IR subfamily might interact with their ligands.

Single-molecule imaging of human insulin receptor ectodomain and its Fab complexes.

Single-molecule images of the IR ectodomain and its complexes with three Fabs have been analyzed by electron microscopy, suggesting that the IR dimer is organized into two layers with the L1/cys-rich/L2 domains occupying the upper region of the U-shaped prism and the fibronectin type III domains and the insert domains located predominantly in the membrane-proximal region.

Hormone-triggered conformational changes within the insulin-receptor ectodomain: requirement for transmembrane anchors.

The results are consistent with a model of receptor function that ensures a global insulin-triggered reorientation of subdomains within the ectodomain moieties while the secondary structure is essentially retained.

The insulin receptor: from protein sequence to structure.

What can be learnt further from the analysis of sequences, about the structure, organization and function of the extracellular regions of the IR family is asked.

Mechanism of transmembrane signaling: insulin binding and the insulin receptor.

The recently solved quaternary structure of the complete dimeric insulin receptor in the presence of insulin has now served as the structural envelope into which individual domains were fitted, and has provided answers on the details of insulin/receptor interactions in the binding site and on the mechanism of transmembrane signaling of this covalent dimer.

Insulin and its receptor: structure, function and evolution

In the absence of a full three-dimensional structure of the insulin–receptor complex, the existing pieces of the puzzle generated by insulin chemists and molecular biologists are assembled in order to generate a plausible mechanistic model of the diabetes interaction that explains its kinetics and negative cooperativity.

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.