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- PDB-3eta: Kinase domain of insulin receptor complexed with a pyrrolo pyridi... -

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Basic information

Entry
Database: PDB / ID: 3eta
TitleKinase domain of insulin receptor complexed with a pyrrolo pyridine inhibitor
Componentsinsulin receptor, kinase domain
KeywordsSIGNALING PROTEIN / TRANSFERASE / 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 / neuronal cell body membrane / adrenal gland development / Signaling by Insulin receptor / IRS activation / amyloid-beta clearance / activation of protein kinase activity / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / transport across blood-brain barrier / insulin receptor substrate binding / epidermis development / positive regulation of glycogen biosynthetic process / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / dendrite membrane / Insulin receptor recycling / insulin-like growth factor receptor binding / receptor-mediated endocytosis / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / learning / caveola / positive regulation of glucose import / 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 / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of nitric oxide biosynthetic process / late endosome / glucose homeostasis / insulin receptor signaling pathway / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / positive regulation of MAPK cascade / protein autophosphorylation / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / carbohydrate metabolic process / positive regulation of cell migration / positive regulation of protein phosphorylation / symbiont entry into host cell / G protein-coupled receptor signaling pathway / axon / protein domain specific binding / external side of plasma membrane / protein phosphorylation / positive regulation of cell population proliferation / protein-containing complex binding / GTP binding / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / extracellular exosome / ATP binding / membrane / identical protein binding / 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-351 / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsPatnaik, S. / Stevens, K. / Gerding, R. / Deanda, F. / Shotwell, B. / Tang, J. / Hamajima, T. / Nakamura, H. / Leesnitzer, A. / Hassell, A. ...Patnaik, S. / Stevens, K. / Gerding, R. / Deanda, F. / Shotwell, B. / Tang, J. / Hamajima, T. / Nakamura, H. / Leesnitzer, A. / Hassell, A. / Shewchuk, L. / Kumar, R. / Lei, H. / Chamberlain, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Discovery of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines as potent inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase.
Authors: Patnaik, S. / Stevens, K.L. / Gerding, R. / Deanda, F. / Shotwell, J.B. / Tang, J. / Hamajima, T. / Nakamura, H. / Leesnitzer, M.A. / Hassell, A.M. / Shewchuck, L.M. / Kumar, R. / Lei, H. / Chamberlain, S.D.
History
DepositionOct 7, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 26, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Jul 24, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.3Sep 6, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: insulin receptor, kinase domain
B: insulin receptor, kinase domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3644
Polymers72,3132
Non-polymers1,0512
Water3,783210
1
A: insulin receptor, kinase domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6822
Polymers36,1561
Non-polymers5261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: insulin receptor, kinase domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6822
Polymers36,1561
Non-polymers5261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1370 Å2
ΔGint-11 kcal/mol
Surface area26890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.105, 94.751, 129.858
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, kinase domain / / E.C.2.7.10.1 / IR / Insulin receptor subunit alpha / Insulin receptor subunit beta


Mass: 36156.285 Da / Num. of mol.: 2 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Plasmid: pFastbac / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf21
References: UniProt: P06213, receptor protein-tyrosine kinase
#2: Chemical ChemComp-351 / 1-(3-{5-[4-(aminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)-3-(2-phenoxyphenyl)urea


Mass: 525.600 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H27N5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 210 / 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: 3.79 Å3/Da / Density % sol: 67.55 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M MOPS pH 7.0, 1.1 M sodium citrate, 1% Jeffamine M89, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 13, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→76.7 Å / Num. all: 31888 / Num. obs: 31888 / % possible obs: 99.5 % / Observed criterion σ(I): 1 / Redundancy: 6.9 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 14.4
Reflection shellResolution: 2.6→2.66 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 2.44 / Num. unique all: 2307 / % possible all: 98.05

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Processing

Software
NameVersionClassification
REFMAC5.2refinement
CNSrefinement
ADSCQuantumdata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1IRK

1irk


Resolution: 2.6→76.7 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.921 / SU B: 13.836 / SU ML: 0.159 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R: 0.352 / ESU R Free: 0.246 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23202 2470 7.2 %RANDOM
Rwork0.20115 ---
obs0.20337 31888 99.56 %-
all-31888 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.234 Å2
Baniso -1Baniso -2Baniso -3
1--1.61 Å20 Å20 Å2
2--2.09 Å20 Å2
3----0.48 Å2
Refinement stepCycle: LAST / Resolution: 2.6→76.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4571 0 80 210 4861
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0214951
X-RAY DIFFRACTIONr_angle_refined_deg0.9991.9776719
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1995616
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.45323.973224
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.4515829
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9571534
X-RAY DIFFRACTIONr_chiral_restr0.0680.2719
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.023974
X-RAY DIFFRACTIONr_nbd_refined0.1820.22251
X-RAY DIFFRACTIONr_nbtor_refined0.2990.23359
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1030.2302
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.110.221
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1570.27
X-RAY DIFFRACTIONr_mcbond_it0.3281.53132
X-RAY DIFFRACTIONr_mcangle_it0.55624893
X-RAY DIFFRACTIONr_scbond_it0.70332073
X-RAY DIFFRACTIONr_scangle_it1.1414.51826
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.373 161 -
Rwork0.339 2307 -
obs-2307 98.05 %
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)
10.7216-0.5831-1.12123.85940.91243.81620.1137-0.14690.01350.06250.1669-0.1294-0.20250.1181-0.2806-0.0868-0.0262-0.0186-0.009-0.0142-0.091253.16620.29513.532
23.32890.9269-2.02532.0955-1.24595.0010.33180.28940.49010.0290.05830.2574-0.5117-0.2045-0.39010.02460.09420.0502-0.08060.11360.008136.38519.57535.972
35.23480.88820.55392.42340.66381.9722-0.05440.1988-0.1858-0.13790.030.0319-0.0157-0.03540.0244-0.13130.0225-0.0277-0.1129-0.038-0.130747.4293.526-3.134
43.5478-0.1639-0.16632.213-0.63811.68310.0195-0.2250.05060.1619-0.01740.0026-0.07770.1005-0.0021-0.11050.010.0167-0.06480.0417-0.171741.4451.51851.672
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A980 - 1082
2X-RAY DIFFRACTION2B980 - 1082
3X-RAY DIFFRACTION3A1083 - 1283
4X-RAY DIFFRACTION4B1083 - 1283

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