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

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Basic information

Entry
Database: PDB / ID: 3ekk
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 / positive regulation of developmental growth / insulin-like growth factor II binding / 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 / positive regulation of developmental growth / insulin-like growth factor II binding / 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 / neuronal cell body membrane / Signaling by Insulin receptor / IRS activation / activation of protein kinase activity / amyloid-beta clearance / positive regulation of respiratory burst / positive regulation of receptor internalization / regulation of embryonic development / transport across blood-brain barrier / insulin receptor substrate binding / positive regulation of glycogen biosynthetic process / epidermis development / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / dendrite membrane / Insulin receptor recycling / neuron projection maintenance / positive regulation of glycolytic process / activation of protein kinase B activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / learning / caveola / positive regulation of glucose import / insulin-like growth factor receptor binding / positive regulation of MAP kinase activity / receptor internalization / receptor protein-tyrosine kinase / memory / cellular response to growth factor stimulus / peptidyl-tyrosine phosphorylation / 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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / lysosome / receptor complex / endosome membrane / positive regulation of cell migration / symbiont entry into host cell / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / protein domain specific binding / external side of plasma membrane / axon / protein phosphorylation / positive regulation of cell population proliferation / protein-containing complex binding / regulation of DNA-templated transcription / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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. / 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-GS2 / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 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. / Sabbatini, P. / Shewchuk, L.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: Potent inhibitors of the IGF-1R receptor tyrosine kinase.
Authors: Chamberlain, S.D. / Wilson, J.W. / Deanda, F. / Patnaik, S. / Redman, A.M. / Yang, B. / Shewchuk, L. / Sabbatini, P. / Leesnitzer, M.A. / Groy, A. / Atkins, C. / Gerding, R. / Hassell, A.M. ...Authors: Chamberlain, S.D. / Wilson, J.W. / Deanda, F. / Patnaik, S. / Redman, A.M. / Yang, B. / Shewchuk, L. / Sabbatini, P. / Leesnitzer, M.A. / Groy, A. / Atkins, C. / Gerding, R. / Hassell, A.M. / Lei, H. / Mook, R.A. / Moorthy, G. / Rowand, J.L. / Stevens, K.L. / Kumar, R. / Shotwell, J.B.
History
DepositionSep 19, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 23, 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)35,3802
Polymers34,8501
Non-polymers5311
Water5,459303
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.251, 70.487, 88.600
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-GS2 / 2-[(2-{[1-(N,N-dimethylglycyl)-5-methoxy-1H-indol-6-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide


Mass: 530.553 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27FN8O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 303 / 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: 52.87 %
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 FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Mar 21, 2008 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.1→55.13 Å / Num. all: 20779 / Num. obs: 20779 / % possible obs: 99.94 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 6.7 % / Rmerge(I) obs: 0.098 / Net I/σ(I): 28
Reflection shellHighest resolution: 2.1 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 6.9 / Num. unique all: 1504 / % possible all: 99.8

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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: 2.1→55.13 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.886 / SU B: 8.622 / SU ML: 0.13 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R: 0.225 / ESU R Free: 0.2 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26021 1133 5.2 %RANDOM
Rwork0.20447 ---
obs0.20723 20779 99.94 %-
all-20779 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.756 Å2
Baniso -1Baniso -2Baniso -3
1--0.07 Å20 Å20 Å2
2--0.31 Å20 Å2
3----0.24 Å2
Refinement stepCycle: LAST / Resolution: 2.1→55.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2239 0 39 303 2581
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222433
X-RAY DIFFRACTIONr_angle_refined_deg1.1051.9743316
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1765303
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.62224.196112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.42115409
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.191516
X-RAY DIFFRACTIONr_chiral_restr0.0690.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021945
X-RAY DIFFRACTIONr_nbd_refined0.170.21171
X-RAY DIFFRACTIONr_nbtor_refined0.2960.21692
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1210.2305
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0820.225
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0850.219
X-RAY DIFFRACTIONr_mcbond_it0.4471.51536
X-RAY DIFFRACTIONr_mcangle_it0.71522406
X-RAY DIFFRACTIONr_scbond_it1.02831045
X-RAY DIFFRACTIONr_scangle_it1.6614.5910
LS refinement shellResolution: 2.1→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.277 91 -
Rwork0.216 1504 -
obs-1504 99.94 %
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)
11.92680.492-0.69532.9657-0.2192.03880.11670.10390.27580.283-0.00870.2144-0.1556-0.1387-0.108-0.0488-0.0180.0221-0.05620.0079-0.0521-6.714227.2241-8.6332
21.75350.04940.25571.30970.08362.2507-0.01380.0720.0443-0.08950.03180.08050.0627-0.0522-0.018-0.0746-0.02330.0066-0.0864-0.0015-0.0639-18.00337.9109-22.6001
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A980 - 1082
2X-RAY DIFFRACTION2A1083 - 1283

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