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- PDB-5hhw: Crystal structure of insulin receptor kinase domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5hhw
TitleCrystal structure of insulin receptor kinase domain in complex with cis-(R)-7-(3-(azetidin-1-ylmethyl)cyclobutyl)-5-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
ComponentsInsulin receptor
KeywordsTRANSFERASE / Inhibitor / Complex / Insulin receptor / 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 / positive regulation of protein-containing complex disassembly / insulin receptor activity / exocrine pancreas development ...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 / positive regulation of protein-containing complex disassembly / insulin receptor activity / exocrine pancreas development / dendritic spine maintenance / cargo receptor activity / insulin binding / adrenal gland development / PTB domain binding / neuronal cell body membrane / Signaling by Insulin receptor / IRS activation / positive regulation of respiratory burst / amyloid-beta clearance / positive regulation of receptor internalization / regulation of embryonic development / insulin receptor substrate binding / epidermis development / protein kinase activator activity / positive regulation of glycogen biosynthetic process / Signal attenuation / heart morphogenesis / transport across blood-brain barrier / phosphatidylinositol 3-kinase binding / Insulin receptor recycling / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / Insulin receptor signalling cascade / positive regulation of glycolytic process / positive regulation of D-glucose import / learning / receptor protein-tyrosine kinase / caveola / cellular response to growth factor stimulus / receptor internalization / memory / male gonad development / cellular response to insulin stimulus / positive regulation of nitric oxide biosynthetic process / insulin receptor signaling pathway / late endosome / glucose homeostasis / amyloid-beta binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / lysosome / positive regulation of canonical NF-kappaB signal transduction / 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 / G protein-coupled receptor signaling pathway / protein domain specific binding / axon / external side of plasma membrane / positive regulation of cell population proliferation / regulation of DNA-templated transcription / symbiont entry into host cell / positive regulation of DNA-templated transcription / GTP binding / protein-containing complex binding / 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 / Fibronectin type III domain / Growth factor receptor cysteine-rich domain superfamily / : / 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-60O / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsScheufler, C. / Izaac, A. / Stauffer, F.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors.
Authors: Stauffer, F. / Cowan-Jacob, S.W. / Scheufler, C. / Furet, P.
History
DepositionJan 11, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.host_org_common_name / _entity_src_gen.pdbx_host_org_strain
Revision 1.2May 1, 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

Downloads & links

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Assembly

Deposited unit
A: Insulin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4493
Polymers34,9391
Non-polymers5102
Water5,765320
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area100 Å2
ΔGint-0 kcal/mol
Surface area15370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.920, 69.160, 89.860
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: 34939.016 Da / Num. of mol.: 1 / Fragment: Kinase domain, residues 1005-1310 / Mutation: C1008S, D1159N
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-60O / 7-[3-(azetidin-1-ylmethyl)cyclobutyl]-5-[3-[[(2~{R})-oxan-2-yl]methoxy]phenyl]pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 447.573 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H33N5O2
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 320 / 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: 2.58 Å3/Da / Density % sol: 52.24 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.5 / Details: 18% Peg3000, 0.1M Tris pH7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 10, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.79→50 Å / Num. obs: 30264 / % possible obs: 87.1 % / Redundancy: 7.16 % / Biso Wilson estimate: 20.39 Å2 / Rsym value: 0.06 / Net I/σ(I): 24.28
Reflection shellResolution: 1.79→1.84 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 5.82 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 1.79→22.77 Å / Cor.coef. Fo:Fc: 0.9502 / Cor.coef. Fo:Fc free: 0.9381 / SU R Cruickshank DPI: 0.122 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.133 / SU Rfree Blow DPI: 0.117 / SU Rfree Cruickshank DPI: 0.112
RfactorNum. reflection% reflectionSelection details
Rfree0.1979 1513 5 %RANDOM
Rwork0.1707 ---
obs0.172 30248 87.12 %-
Displacement parametersBiso mean: 22.18 Å2
Baniso -1Baniso -2Baniso -3
1-0.7086 Å20 Å20 Å2
2--1.1883 Å20 Å2
3----1.8969 Å2
Refine analyzeLuzzati coordinate error obs: 0.184 Å
Refinement stepCycle: 1 / Resolution: 1.79→22.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2443 0 37 320 2800
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012545HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.953451HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d891SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes63HARMONIC2
X-RAY DIFFRACTIONt_gen_planes367HARMONIC5
X-RAY DIFFRACTIONt_it2545HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.43
X-RAY DIFFRACTIONt_other_torsion15.12
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion314SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3262SEMIHARMONIC4
LS refinement shellResolution: 1.79→1.85 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2274 169 5.01 %
Rwork0.1856 3203 -
all0.1877 3372 -
obs--87.12 %
Refinement TLS params.Method: refined / Origin x: -14.3489 Å / Origin y: -15.4953 Å / Origin z: 18.2125 Å
111213212223313233
T-0.0479 Å2-0.0016 Å2-0.0126 Å2--0.0443 Å20.0013 Å2---0.0366 Å2
L0.4869 °2-0.2621 °2-0.1932 °2-0.8499 °20.1153 °2--0.6406 °2
S-0.0384 Å °-0.0247 Å °0.0008 Å °0.0338 Å °0.0176 Å °0.0399 Å °0.033 Å °0.0221 Å °0.0208 Å °
Refinement TLS groupSelection details: { A|* L|* }

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