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- PDB-4ibm: Crystal structure of insulin receptor kinase domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 4ibm
TitleCrystal structure of insulin receptor kinase domain in complex with an inhibitor Irfin-1
ComponentsInsulin receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / irk / kinase / ATP binding / Phosphorylation / Membrane / 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 / insulin receptor complex / insulin-like growth factor I binding / exocrine pancreas development / positive regulation of protein-containing complex disassembly / dendritic spine maintenance ...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 / insulin receptor complex / insulin-like growth factor I binding / exocrine pancreas development / positive regulation of protein-containing complex disassembly / dendritic spine maintenance / cargo receptor activity / insulin binding / neuronal cell body membrane / adrenal gland development / PTB domain binding / Signaling by Insulin receptor / IRS activation / positive regulation of respiratory burst / amyloid-beta clearance / regulation of embryonic development / positive regulation of receptor internalization / protein kinase activator activity / insulin receptor substrate binding / epidermis development / positive regulation of glycogen biosynthetic process / Signal attenuation / phosphatidylinositol 3-kinase binding / transport across blood-brain barrier / heart morphogenesis / activation of protein kinase B activity / Insulin receptor recycling / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / positive regulation of MAP kinase activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / positive regulation of glycolytic process / learning / positive regulation of D-glucose import / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / caveola / receptor internalization / memory / cellular response to insulin stimulus / male gonad development / positive regulation of nitric oxide biosynthetic process / late endosome / insulin receptor signaling pathway / glucose homeostasis / amyloid-beta binding / positive regulation of protein phosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation / protein tyrosine kinase activity / positive regulation of canonical NF-kappaB signal transduction / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / endosome membrane / positive regulation of cell migration / protein phosphorylation / G protein-coupled receptor signaling pathway / protein domain specific binding / symbiont entry into host cell / axon / external side of plasma membrane / positive regulation of cell population proliferation / regulation of DNA-templated transcription / protein-containing complex binding / GTP binding / positive regulation of DNA-templated transcription / 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 / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-IR1 / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsWu, J. / Anastassiadis, T. / Duong-Ly, K.C. / Peterson, J.R.
CitationJournal: J.Biol.Chem. / Year: 2013
Title: A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor.
Authors: Anastassiadis, T. / Duong-Ly, K.C. / Deacon, S.W. / Lafontant, A. / Ma, H. / Devarajan, K. / Dunbrack, R.L. / Wu, J. / Peterson, J.R.
History
DepositionDec 8, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 21, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2013Group: Database references
Revision 1.2Nov 20, 2013Group: Database references
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Insulin receptor
B: Insulin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,2724
Polymers69,6202
Non-polymers6532
Water9,980554
1
A: Insulin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1362
Polymers34,8101
Non-polymers3261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Insulin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1362
Polymers34,8101
Non-polymers3261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.838, 89.210, 142.193
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Insulin receptor / IR / Insulin receptor subunit alpha / Insulin receptor subunit beta


Mass: 34809.793 Da / Num. of mol.: 2 / Mutation: K1278N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P06213, receptor protein-tyrosine kinase
#2: Chemical ChemComp-IR1 / 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3H-pyrazolo[3,4-c]pyridazin-3-one


Mass: 326.312 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H10N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 554 / 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: 2.32 Å3/Da / Density % sol: 46.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 0.1 M Sodium cacodylate pH 6.5, 23% PEG-4000, 10% Ethylene glycol, and 0.03 M Glycyl-glycyl-glycine, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4C / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Apr 21, 2011
RadiationMonochromator: Single crystal bender / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 60964 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.8→1.83 Å / % possible all: 97.8

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Processing

Software
NameVersionClassification
MAR345data collection
MOLREPphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→50 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.938 / SU B: 5.295 / SU ML: 0.076 / Cross valid method: THROUGHOUT / ESU R: 0.128 / ESU R Free: 0.122 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21846 3076 5.1 %RANDOM
Rwork0.1821 ---
obs0.18392 57490 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.514 Å2
Baniso -1Baniso -2Baniso -3
1--0.61 Å20 Å20 Å2
2---0.13 Å20 Å2
3---0.74 Å2
Refinement stepCycle: LAST / Resolution: 1.8→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4679 0 50 554 5283
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224901
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.331.9726657
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9835612
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.04724.036223
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.39315836
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2081532
X-RAY DIFFRACTIONr_chiral_restr0.0860.2721
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213749
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6331.52992
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.16624832
X-RAY DIFFRACTIONr_scbond_it1.81731909
X-RAY DIFFRACTIONr_scangle_it2.9984.51815
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.304 216 -
Rwork0.262 4035 -
obs--96.59 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.14780.30530.04611.03330.4930.9320.02110.0857-0.0986-0.05890.0155-0.0497-0.03140.0159-0.03660.03290.0177-0.00230.02670.00590.0293-3.2553-6.015614.672
21.2768-0.3196-0.17820.8095-0.0780.8292-0.0067-0.08380.00640.0889-0.01640.0064-0.0657-0.00780.02310.0347-0.0209-0.00530.02680.00130.0165-20.8178-12.552745.299
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A982 - 1282
2X-RAY DIFFRACTION2B987 - 1283

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