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- PDB-1gag: CRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH ... -

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Basic information

Entry
Database: PDB / ID: 1gag
TitleCRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH A BISUBSTRATE INHIBITOR
Components
  • BISUBSTRATE PEPTIDE INHIBITOR
  • INSULIN RECEPTOR, TYROSINE KINASE DOMAIN
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PROTEIN KINASE INHIBITOR / TYROSINE KINASE / transferase / signaling protein / transferase-transferase inhibitor complex
Function / homology
Function and homology information


regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly ...regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / cargo receptor activity / dendritic spine maintenance / insulin binding / PTB domain binding / adrenal gland development / Signaling by Insulin receptor / IRS activation / activation of protein kinase activity / neuronal cell body membrane / amyloid-beta clearance / positive regulation of respiratory burst / positive regulation of receptor internalization / regulation of embryonic development / insulin receptor substrate binding / transport across blood-brain barrier / positive regulation of glycogen biosynthetic process / epidermis development / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / Insulin receptor recycling / dendrite membrane / insulin-like growth factor receptor binding / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / positive regulation of MAP kinase activity / learning / caveola / positive regulation of glucose import / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / receptor internalization / memory / cellular response to growth factor stimulus / male gonad development / positive regulation of nitric oxide biosynthetic process / glucose homeostasis / late endosome / insulin receptor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / amyloid-beta binding / protein tyrosine kinase activity / protein autophosphorylation / receptor complex / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / endosome membrane / lysosome / positive regulation of cell migration / positive regulation of protein phosphorylation / symbiont entry into host cell / protein domain specific binding / G protein-coupled receptor signaling pathway / protein phosphorylation / external side of plasma membrane / axon / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / regulation of DNA-templated transcription / protein-containing complex binding / GTP binding / extracellular exosome / ATP binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats ...Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Growth factor receptor cysteine-rich domain superfamily / : / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Immunoglobulin-like fold / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-112 / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.7 Å
AuthorsParang, K. / Till, J.H. / Ablooglu, A.J. / Kohanski, R.A. / Hubbard, S.R. / Cole, P.A.
Citation
Journal: Nat.Struct.Biol. / Year: 2001
Title: Mechanism-based design of a protein kinase inhibitor.
Authors: Parang, K. / Till, J.H. / Ablooglu, A.J. / Kohanski, R.A. / Hubbard, S.R. / Cole, P.A.
#1: Journal: Embo J. / Year: 1997
Title: Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog
Authors: Hubbard, S.R.
History
DepositionNov 29, 2000Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2001Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Oct 27, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Aug 9, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: INSULIN RECEPTOR, TYROSINE KINASE DOMAIN
B: BISUBSTRATE PEPTIDE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9855
Polymers36,3562
Non-polymers6293
Water41423
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2890 Å2
ΔGint-37 kcal/mol
Surface area14940 Å2
MethodPISA
2
A: INSULIN RECEPTOR, TYROSINE KINASE DOMAIN
B: BISUBSTRATE PEPTIDE INHIBITOR
hetero molecules

A: INSULIN RECEPTOR, TYROSINE KINASE DOMAIN
B: BISUBSTRATE PEPTIDE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,97010
Polymers72,7124
Non-polymers1,2586
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_465y-1,x+1,-z1
Buried area7540 Å2
ΔGint-86 kcal/mol
Surface area28110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.3, 66.3, 138.1
Angle α, β, γ (deg.)90, 90, 120
Int Tables number154
Cell settingtrigonal
Space group name H-MP3221

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Components

#1: Protein INSULIN RECEPTOR, TYROSINE KINASE DOMAIN / E.C.2.7.1.112 / IR


Mass: 35032.738 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN / Mutation: C981S, Y984F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P06213, EC: 2.7.1.112
#2: Protein/peptide BISUBSTRATE PEPTIDE INHIBITOR


Mass: 1323.495 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: PHE107 OF PEPTIDE 13-MER MODIFIED BY ATP GAMMA S PLUS FOUR-ATOM LINKER, RESIDUE 112
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-112 / THIOPHOSPHORIC ACID O-((ADENOSYL-PHOSPHO)PHOSPHO)-S-ACETAMIDYL-DIESTER


Mass: 580.298 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H19N6O13P3S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.4 Å3/Da / Density % sol: 50 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: PEG 8000, Tris-HCl, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K
Crystal grow
*PLUS
Temperature: 4 ℃
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
110 mg/mlprotein1drop
20.400 mMinhibitor1drop
31.2 mM1dropMgCl2
418 %(w/v)PEG80001reservoir
5100 mMTris-HCl1reservoirpH7.5

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Jul 3, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.7→30 Å / Num. all: 42217 / Num. obs: 42217 / % possible obs: 96.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.4 % / Rmerge(I) obs: 0.114 / Net I/σ(I): 7.6
Reflection shellResolution: 2.7→2.8 Å / Rmerge(I) obs: 0.339 / % possible all: 91.9
Reflection
*PLUS
Lowest resolution: 30 Å / Num. obs: 9633 / Num. measured all: 42217
Reflection shell
*PLUS
% possible obs: 91.9 %

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Processing

Software
NameClassification
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1IR3

1ir3


Resolution: 2.7→30 Å / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.269 501 5.4 %RANDOM
Rwork0.214 ---
all0.214 9342 --
obs0.214 9342 91.8 %-
Solvent computationSolvent model: CNS / Bsol: 10.14 Å2 / ksol: 0.312 e/Å3
Displacement parametersBiso mean: 20.6 Å2
Baniso -1Baniso -2Baniso -3
1-4.931 Å2-4.324 Å20 Å2
2--4.931 Å20 Å2
3----9.862 Å2
Refinement stepCycle: LAST / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2460 0 37 23 2520
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d22.4
X-RAY DIFFRACTIONc_improper_angle_d0.753
X-RAY DIFFRACTIONc_mcbond_it0.9641.5
X-RAY DIFFRACTIONc_mcangle_it1.622
X-RAY DIFFRACTIONc_scbond_it1.5912
X-RAY DIFFRACTIONc_scangle_it2.382.5
Software
*PLUS
Name: CNS / Classification: refinement
Refinement
*PLUS
Highest resolution: 2.7 Å / Lowest resolution: 30 Å / σ(F): 0 / % reflection Rfree: 5.4 %
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 20.6 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.4
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.753
X-RAY DIFFRACTIONc_mcbond_it1.5
X-RAY DIFFRACTIONc_scbond_it2
X-RAY DIFFRACTIONc_mcangle_it2
X-RAY DIFFRACTIONc_scangle_it2.5

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