3W11 | pdb_00003w11

Insulin receptor ectodomain construct comprising domains L1-CR in complex with human insulin, Alpha-CT peptide(704-719) and FAB 83-7


Experimental Data Snapshot

  • Method:&nbspX-RAY DIFFRACTION
  • Resolution:&nbsp3.90 Å
  • R-Value Free:&nbsp
    0.292 (Depositor), 0.330 (DCC)&nbsp
  • R-Value Work:&nbsp
    0.264 (Depositor), 0.290 (DCC)&nbsp
  • R-Value Observed:&nbsp
    0.266&nbsp(Depositor)&nbsp

Starting Models: experimental
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Ligand Structure Quality Assessment&nbsp


This is version 2.2 of the entry. See complete&nbsphistory.&nbsp


Literature

How insulin engages its primary binding site on the insulin receptor

Menting, J.G.,&nbspWhittaker, J.,&nbspMargetts, M.B.,&nbspWhittaker, L.J.,&nbspKong, G.K.-W.,&nbspSmith, B.J.,&nbspWatson, C.J.,&nbspZakova, L.,&nbspKletvikova, E.,&nbspJiracek, J.,&nbspChan, S.J.,&nbspSteiner, D.F.,&nbspDodson, G.G.,&nbspBrzozowski, A.M.,&nbspWeiss, M.A.,&nbspWard, C.W.,&nbspLawrence, M.C.

(2013) Nature&nbsp493: 241-245

  • DOI:&nbsphttps://doi.org/10.1038/nature11781
  • Primary Citation of Related Structures: &nbsp
    3W11, 3W12, 3W13, 5KQV

  • PubMed Abstract:&nbsp

    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 α-chain (αCT) 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 αCT segment displaces the B-chain C-terminal β-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.


  • Organizational Affiliation:&nbsp

    Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Insulin A chain21Homo sapiensMutation(s): 0&nbsp
Gene Names:&nbspINS
UniProt & NIH Common Fund Data Resources
Find proteins for&nbspP01308&nbsp(Homo sapiens)
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Go to UniProtKB: &nbspP01308
PHAROS: &nbspP01308
GTEx: &nbspENSG00000254647&nbsp
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UniProt GroupP01308
Sequence Annotations
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Insulin B chain30Homo sapiensMutation(s): 0&nbsp
Gene Names:&nbspINS
UniProt & NIH Common Fund Data Resources
Find proteins for&nbspP01308&nbsp(Homo sapiens)
Explore&nbspP01308&nbsp
Go to UniProtKB: &nbspP01308
PHAROS: &nbspP01308
GTEx: &nbspENSG00000254647&nbsp
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UniProt GroupP01308
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
monoclonal antibody fab 83-7 fragment - heavy chain118Mus musculusMutation(s): 0&nbsp
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
monoclonal antibody fab 83-7 fragment - light chain114Mus musculusMutation(s): 0&nbsp
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Insulin receptor domains L1-CR310Homo sapiensMutation(s): 0&nbsp
Gene Names:&nbspINSR
EC:&nbsp2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for&nbspP06213&nbsp(Homo sapiens)
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PHAROS: &nbspP06213
GTEx: &nbspENSG00000171105&nbsp
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UniProt GroupP06213
Glycosylation
Glycosylation Sites: 5Go to GlyGen: P06213-1
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Insulin receptor alpha-CT peptide16Homo sapiensMutation(s): 0&nbsp
EC:&nbsp2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for&nbspP06213&nbsp(Homo sapiens)
Explore&nbspP06213&nbsp
Go to UniProtKB: &nbspP06213
PHAROS: &nbspP06213
GTEx: &nbspENSG00000171105&nbsp
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UniProt GroupP06213
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Oligosaccharides

Help

Entity ID: 7
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
G
4N-Glycosylation
Glycosylation Resources
GlyTouCan: &nbspG81315DD
GlyCosmos: &nbspG81315DD
GlyGen: &nbspG81315DD
Entity ID: 8
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
H
3N-Glycosylation
Glycosylation Resources
GlyTouCan: &nbspG15407YE
GlyCosmos: &nbspG15407YE
GlyGen: &nbspG15407YE
Experimental Data & Validation

Experimental Data

  • Method:&nbspX-RAY DIFFRACTION
  • Resolution:&nbsp3.90 Å
  • R-Value Free:&nbsp 0.292 (Depositor), 0.330 (DCC)&nbsp
  • R-Value Work:&nbsp 0.264 (Depositor), 0.290 (DCC)&nbsp
  • R-Value Observed:&nbsp0.266&nbsp(Depositor)&nbsp
Space Group:&nbspP 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 168.91α = 90
b = 168.91β = 90
c = 168.91γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing
BUSTERrefinement

Structure Validation

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Ligand Structure Quality Assessment&nbsp


Entry History&nbsp

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-01-09
    Type: Initial release
  • Version 1.1: 2013-01-16
    Changes: Database references
  • Version 1.2: 2013-09-04
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-11-08
    Changes: Data collection, Database references, Refinement description, Structure summary
  • Version 2.2: 2024-10-16
    Changes: Structure summary