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- PDB-5e1s: The Crystal structure of INSR Tyrosine Kinase in complex with the... -

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Basic information

Entry
Database: PDB / ID: 5e1s
TitleThe Crystal structure of INSR Tyrosine Kinase in complex with the Inhibitor BI 885578
ComponentsInsulin receptor
KeywordsTRANSFERASE / Kinase / INSR / IGF-1R / Inhibitor
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 / regulation of embryonic development / positive regulation of receptor internalization / 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 / insulin-like growth factor receptor binding / 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 / 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 / positive regulation of nitric oxide biosynthetic process / male gonad development / 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 / axon / external side of plasma membrane / 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 / 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-5JA / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.264 Å
AuthorsKessler, D. / Zahn, S. / Sanderson, M. / Wolkerstorfer, B.
CitationJournal: Mol.Cancer Ther. / Year: 2015
Title: BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis.
Authors: Sanderson, M.P. / Apgar, J. / Garin-Chesa, P. / Hofmann, M.H. / Kessler, D. / Quant, J. / Savchenko, A. / Schaaf, O. / Treu, M. / Tye, H. / Zahn, S.K. / Zoephel, A. / Haaksma, E. / Adolf, G.R. / Kraut, N.
History
DepositionSep 30, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Oct 14, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 16, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Insulin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4802
Polymers34,9521
Non-polymers5281
Water2,468137
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.550, 70.370, 87.850
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


Mass: 34951.949 Da / Num. of mol.: 1
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-5JA / (5R)-N-(1-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-1H-pyrazol-3-yl)-5,8-dimethyl-9-phenyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinazolin-2-amine


Mass: 527.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H37N9O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 137 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.5 Å3/Da / Density % sol: 50.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 25% PEG 8000, 0.1M TRIS pH 7.3, 50mM NaCl, 5 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.264→37.26 Å / Num. all: 16922 / Num. obs: 16922 / % possible obs: 100 % / Redundancy: 6.4 % / Biso Wilson estimate: 46.57 Å2 / Rmerge(I) obs: 0.085 / Rsym value: 0.085 / Net I/av σ(I): 14.3 / Net I/σ(I): 14.3
Reflection shellResolution: 2.264→2.272 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.636 / Mean I/σ(I) obs: 3 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1IRK

1irk


Resolution: 2.264→37.26 Å / Cor.coef. Fo:Fc: 0.9234 / Cor.coef. Fo:Fc free: 0.8922 / SU R Cruickshank DPI: 0.282 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.302 / SU Rfree Blow DPI: 0.229 / SU Rfree Cruickshank DPI: 0.225
RfactorNum. reflection% reflectionSelection details
Rfree0.262 851 5.04 %RANDOM
Rwork0.2126 ---
obs0.215 16877 99.38 %-
Displacement parametersBiso mean: 48.74 Å2
Baniso -1Baniso -2Baniso -3
1-7.3803 Å20 Å20 Å2
2---6.581 Å20 Å2
3----0.7993 Å2
Refine analyzeLuzzati coordinate error obs: 0.331 Å
Refinement stepCycle: LAST / Resolution: 2.264→37.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2269 0 39 137 2445
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082366HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.983204HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d838SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes61HARMONIC2
X-RAY DIFFRACTIONt_gen_planes336HARMONIC5
X-RAY DIFFRACTIONt_it2366HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.54
X-RAY DIFFRACTIONt_other_torsion16.76
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion289SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2743SEMIHARMONIC4
LS refinement shellResolution: 2.26→2.42 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2507 160 5.5 %
Rwork0.2276 2747 -
all0.2289 2907 -
obs--99.38 %
Refinement TLS params.Method: refined / Origin x: 13.7278 Å / Origin y: 14.502 Å / Origin z: 17.8066 Å
111213212223313233
T-0.1814 Å2-0.0058 Å20.0154 Å2--0.1119 Å2-0.0089 Å2---0.1278 Å2
L1.9788 °2-1.0229 °2-0.1155 °2-1.891 °20.2039 °2--2.1436 °2
S-0.0586 Å °-0.0461 Å °0.1267 Å °0.0671 Å °0.0645 Å °-0.1357 Å °-0.0266 Å °-0.1118 Å °-0.0059 Å °
Refinement TLS groupSelection details: { A|* }

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