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- PDB-8di2: Site 2 insulin receptor binding peptide IM459N21 -

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Basic information

Entry
Database: PDB / ID: 8di2
TitleSite 2 insulin receptor binding peptide IM459N21
ComponentsSite 2 binding peptide IM459N21
KeywordsSIGNALING PROTEIN / Insulin receptor / Receptor / tyrosine kinase
Biological speciessynthetic construct (others)
MethodSOLUTION NMR / molecular dynamics
AuthorsLawrence, M.C. / Hu, H. / Martinez, F.J. / Espinosa, J.F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2022
Title: Activation of the human insulin receptor by non-insulin-related peptides.
Authors: Nicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David ...Authors: Nicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David G Barrett / Michael C Lawrence /
Abstract: The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in ...The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helical binding motifs that are each potentially mimicable by small molecules. The resultant conformation of the receptor is distinct from-but related to-those in extant three-dimensional structures of the insulin-complexed receptor. Our findings thus illuminate unexplored pathways for controlling the signalling of the insulin receptor as well as opportunities for development of insulin mimetics.
History
DepositionJun 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Site 2 binding peptide IM459N21


Theoretical massNumber of molelcules
Total (without water)2,6301
Polymers2,6301
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area180 Å2
ΔGint-1 kcal/mol
Surface area2300 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)16 / 16all calculated structures submitted
RepresentativeModel #1fewest violations

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Components

#1: Protein/peptide Site 2 binding peptide IM459N21


Mass: 2630.088 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D 1H-1H COSY
121isotropic12D 1H-1H TOCSY
131isotropic12D 1H-1H NOESY
141isotropic12D 1H-1H NOESY
151isotropic12D 1H-13C HSQC aliphatic

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Sample preparation

DetailsType: solution
Contents: 20 mM [U-2H] Tris, 100 mM sodium chloride, 0.75 mM peptide, 95% H2O/5% D2O
Details: The peptide concentration was 0.75 mM / Label: IM459N21 / Solvent system: 95% H2O/5% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
20 mMTris[U-2H]1
100 mMsodium chloridenatural abundance1
0.75 mMpeptidenatural abundance1
Sample conditionsDetails: 20 mM Tris-d11, 100 mM NaCl, 5% D2O / Ionic strength: 100 mM / Label: Standard buffer / pH: 7.4 / Pressure: 1 atm / Temperature: 298 K

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NMR measurement

NMR spectrometerType: Bruker AVANCE III / Manufacturer: Bruker / Model: AVANCE III / Field strength: 600 MHz

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Processing

NMR software
NameVersionDeveloperClassification
GROMACS5.0.7Mark Abraham, Berk Hess, David van der Spoel, and Erik Lindahlrefinement
GROMACS5.0.7Mark Abraham, Berk Hess, David van der Spoel, and Erik Lindahlstructure calculation
CcpNmr Analysis2CCPNchemical shift assignment
CcpNmr Analysis2CCPNpeak picking
RefinementMethod: molecular dynamics / Software ordinal: 1
NMR representativeSelection criteria: fewest violations
NMR ensembleConformer selection criteria: all calculated structures submitted
Conformers calculated total number: 16 / Conformers submitted total number: 16

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