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- PDB-3ekn: Insulin receptor kinase complexed with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 3ekn
TitleInsulin receptor kinase complexed with an inhibitor
ComponentsInsulin receptor
KeywordsTRANSFERASE / insulin / tyrosine kinase / ATP-binding / Carbohydrate metabolism / Cleavage on pair of basic residues / Diabetes mellitus / Disease mutation / Glycoprotein / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Receptor / Transmembrane / Tyrosine-protein kinase
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-GS3 / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsChamberlain, S. / Atkins, C. / Deanda, F. / Dumble, M. / Gerding, R. / Groy, A. / Korenchuk, S. / Kumar, R. / Lei, H. / Mook, R. ...Chamberlain, S. / Atkins, C. / Deanda, F. / Dumble, M. / Gerding, R. / Groy, A. / Korenchuk, S. / Kumar, R. / Lei, H. / Mook, R. / Moorthy, G. / Redman, A. / Rowland, J. / Shewchuk, L.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity.
Authors: Chamberlain, S.D. / Redman, A.M. / Wilson, J.W. / Deanda, F. / Shotwell, J.B. / Gerding, R. / Lei, H. / Yang, B. / Stevens, K.L. / Hassell, A.M. / Shewchuk, L.M. / Leesnitzer, M.A. / Smith, ...Authors: Chamberlain, S.D. / Redman, A.M. / Wilson, J.W. / Deanda, F. / Shotwell, J.B. / Gerding, R. / Lei, H. / Yang, B. / Stevens, K.L. / Hassell, A.M. / Shewchuk, L.M. / Leesnitzer, M.A. / Smith, J.L. / Sabbatini, P. / Atkins, C. / Groy, A. / Rowand, J.L. / Kumar, R. / Mook, R.A. / Moorthy, G. / Patnaik, S.
History
DepositionSep 19, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 30, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: 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
Revision 1.3Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Insulin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3682
Polymers34,8501
Non-polymers5191
Water3,981221
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.092, 69.522, 89.961
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: 34849.793 Da / Num. of mol.: 1 / Fragment: kinase domain / Mutation: C1008S, D1159N
Source method: isolated from a genetically manipulated source
Details: Expressed as a 6xHis-TEV fusion protein. His tag removed prior to crystallization.
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Plasmid: pFastbac / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P06213, receptor protein-tyrosine kinase
#2: Chemical ChemComp-GS3 / 2-fluoro-6-{[2-({2-methoxy-4-[4-(1-methylethyl)piperazin-1-yl]phenyl}amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}benzamide


Mass: 518.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H31FN8O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 221 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHERE IS A K->N SEQUENCE CONFLICT IN UNIPROT DATABASE AT RESIDUE 1278.

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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: 2.61 Å3/Da / Density % sol: 52.81 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M MOPS, 1.0 M Na3citrate, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Mar 17, 2007 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.2→55.05 Å / Num. all: 15718 / Num. obs: 15718 / % possible obs: 86.82 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.9 % / Rmerge(I) obs: 0.059 / Net I/σ(I): 24
Reflection shellResolution: 2.2→2.25 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.2 / Mean I/σ(I) obs: 7.3 / Num. unique all: 638 / % possible all: 48

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1P14

1p14


Resolution: 2.2→55.05 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.897 / SU B: 13.695 / SU ML: 0.185 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R: 0.352 / ESU R Free: 0.263 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2738 851 5.1 %RANDOM
Rwork0.21063 ---
obs0.21378 15718 86.82 %-
all-15718 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.634 Å2
Baniso -1Baniso -2Baniso -3
1--0.53 Å20 Å20 Å2
2---0.27 Å20 Å2
3---0.8 Å2
Refinement stepCycle: LAST / Resolution: 2.2→55.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2346 0 38 221 2605
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222474
X-RAY DIFFRACTIONr_angle_refined_deg1.261.9783362
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6075305
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.93124.123114
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.50115420
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7661516
X-RAY DIFFRACTIONr_chiral_restr0.0850.2362
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021941
X-RAY DIFFRACTIONr_nbd_refined0.1840.21169
X-RAY DIFFRACTIONr_nbtor_refined0.3040.21700
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.2214
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1280.246
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0940.210
X-RAY DIFFRACTIONr_mcbond_it0.4721.51539
X-RAY DIFFRACTIONr_mcangle_it0.822421
X-RAY DIFFRACTIONr_scbond_it1.26131077
X-RAY DIFFRACTIONr_scangle_it1.9834.5936
LS refinement shellResolution: 2.2→2.258 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.583 31 -
Rwork0.462 638 -
obs-638 48.03 %
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)
13.0414-0.18851.88513.06242.52816.276-0.2143-0.03890.2337-0.2446-0.05040.2135-0.42470.03930.2647-0.06230.048-0.0273-0.1088-0.0117-0.09611.822926.69619.1519
23.195.21852.601423.751114.25529.73340.0816-0.2205-0.30050.27490.1057-0.687-0.10750.3993-0.1872-0.0154-0.0228-0.0651-0.0196-0.00150.02115.96932.126410.3662
34.4361-1.6882-1.24254.89490.81132.6342-0.03820.08260.0961-0.4017-0.02540.0332-0.20620.03240.0636-0.10140.0275-0.036-0.0952-0.0036-0.18956.806222.01688.8333
42.3506-0.13860.40271.6708-0.67562.2003-0.0529-0.13870.08220.20880.0968-0.0629-0.1189-0.0336-0.0438-0.10160.03790.0024-0.11260.0012-0.096118.40589.083822.1625
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A979 - 1031
2X-RAY DIFFRACTION2A1032 - 1052
3X-RAY DIFFRACTION3A1053 - 1082
4X-RAY DIFFRACTION4A1083 - 1283

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