3W11: Insulin Receptor Ectodomain Construct Comprising Domains L1-cr In Complex With Human Insulin, Alpha-ct Peptide(704-719) And Fab 83-7

Citation:
Abstract
Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal alpha-chain (alphaCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The alphaCT segment displaces the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.
PDB ID: 3W11Download
MMDB ID: 106470
PDB Deposition Date: 2012/11/6
Updated in MMDB: 2013/09
Experimental Method:
x-ray diffraction
Resolution: 3.9  Å
Source Organism:
Mus musculus
Similar Structures:
Biological Unit for 3W11: hexameric; determined by author
Molecular Components in 3W11
Label Count Molecule
Proteins (6 molecules)
1
Insulin a Chain(Gene symbol: INS)
Molecule annotation
1
Insulin B Chain(Gene symbol: INS)
Molecule annotation
1
Monoclonal Antibody FAB 83-7 Fragment - Heavy Chain
Molecule annotation
1
Monoclonal Antibody FAB 83-7 Fragment - Light Chain
Molecule annotation
1
Insulin Receptor Domains L1-cr(Gene symbol: INSR)
Molecule annotation
1
Insulin Receptor Alpha-ct Peptide(Gene symbol: INSR)
Molecule annotation
Chemicals (10 molecules)
1
7
2
2
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.