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- PDB-5hcx: EGFR kinase domain mutant "TMLR" with azabenzimidazole compound 7 -

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Basic information

Entry
Database: PDB / ID: 5hcx
TitleEGFR kinase domain mutant "TMLR" with azabenzimidazole compound 7
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / PTK6 promotes HIF1A stabilization / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / Signaling by ERBB4 / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / protein insertion into membrane / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / GAB1 signalosome / positive regulation of bone resorption / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / positive regulation of DNA repair / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / neuron projection morphogenesis / positive regulation of epithelial cell proliferation / basal plasma membrane / positive regulation of superoxide anion generation / liver regeneration / epithelial cell proliferation / Signal transduction by L1 / positive regulation of DNA replication / neurogenesis / positive regulation of protein localization to plasma membrane / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of smooth muscle cell proliferation / cellular response to amino acid stimulus / lung development / cellular response to estradiol stimulus / EGFR downregulation / clathrin-coated endocytic vesicle membrane / synaptic membrane / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 TMD/JMD mutants / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / 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 / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / positive regulation of peptidyl-serine phosphorylation
Similarity search - Function
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / 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 / : / 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. / 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-60B / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsEigenbrot, C. / Yu, C.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor.
Authors: Chan, B.K. / Hanan, E.J. / Bowman, K.K. / Bryan, M.C. / Burdick, D. / Chan, E. / Chen, Y. / Clausen, S. / Dela Vega, T. / Dotson, J. / Eigenbrot, C. / Elliott, R.L. / Heald, R.A. / Jackson, ...Authors: Chan, B.K. / Hanan, E.J. / Bowman, K.K. / Bryan, M.C. / Burdick, D. / Chan, E. / Chen, Y. / Clausen, S. / Dela Vega, T. / Dotson, J. / Eigenbrot, C. / Elliott, R.L. / Heald, R.A. / Jackson, P.S. / Knight, J.D. / La, H. / Lainchbury, M.D. / Malek, S. / Purkey, H.E. / Schaefer, G. / Schmidt, S. / Seward, E.M. / Sideris, S. / Shao, L. / Wang, S. / Yeap, S.K. / Yen, I. / Yu, C. / Heffron, T.P.
History
DepositionJan 4, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 7, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 26, 2016Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0843
Polymers37,5491
Non-polymers5352
Water1267
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area190 Å2
ΔGint-14 kcal/mol
Surface area15310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.744, 146.744, 146.744
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23

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Components

#1: Protein Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37549.398 Da / Num. of mol.: 1 / Mutation: T790M,L858R,A865E, A866E, A867K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-60B / ~{N}-[2-(1-cyclopropylsulfonylpyrazol-4-yl)pyrimidin-4-yl]-2-methyl-1-propan-2-yl-imidazo[4,5-c]pyridin-6-amine


Mass: 438.506 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22N8O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 3.51 Å3/Da / Density % sol: 64.92 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: PEG 10K, ethylene glycol

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 11, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.6→24.08 Å / Num. all: 15892 / Num. obs: 15892 / % possible obs: 98 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 6.2 % / Biso Wilson estimate: 77.22 Å2 / Rsym value: 0.094 / Net I/σ(I): 16.7
Reflection shellResolution: 2.6→2.7 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.816 / Mean I/σ(I) obs: 2.2 / % possible all: 99.5

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB 5EM5

5em5


Resolution: 2.6→24.08 Å / Cor.coef. Fo:Fc: 0.9523 / Cor.coef. Fo:Fc free: 0.9395 / SU R Cruickshank DPI: 0.315 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.3 / SU Rfree Blow DPI: 0.221 / SU Rfree Cruickshank DPI: 0.228
RfactorNum. reflection% reflectionSelection details
Rfree0.2229 665 4.18 %RANDOM
Rwork0.1922 ---
obs0.1935 15892 97.6 %-
Displacement parametersBiso mean: 72.8 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.393 Å
Refinement stepCycle: 1 / Resolution: 2.6→24.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2389 0 36 7 2432
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092479HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.093360HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d869SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes57HARMONIC2
X-RAY DIFFRACTIONt_gen_planes345HARMONIC5
X-RAY DIFFRACTIONt_it2479HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.79
X-RAY DIFFRACTIONt_other_torsion18.57
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion319SEMIHARMONIC5
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_contact2795SEMIHARMONIC4
LS refinement shellResolution: 2.6→2.78 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2601 109 3.81 %
Rwork0.227 2753 -
all0.2284 2862 -
obs--97.6 %
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)
12.48620.812-0.89341.2430.24874.80360.0059-0.21550.1273-0.1144-0.0528-0.2252-0.24530.54420.047-0.042-0.10590.0529-0.06530.0378-0.05-55.2797.249-30.411
21.94520.9793-0.58154.4023-0.89911.4815-0.1476-0.1651-0.2862-0.3083-0.1176-0.53130.14630.20740.2652-0.0991-0.01770.0935-0.07980.0654-0.1421-61.428-15.914-22.047
30.15590.3535-0.1940.52760.83770.88630.0018-0.03480.02410.0289-0.0001-0.00150.0012-0.0085-0.00170.1059-0.0878-0.03190.05560.0214-0.0204-65.183.563-6.224
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|696 - A|786 A|1006 - A|1018 }A696 - 786
2X-RAY DIFFRACTION1{ A|696 - A|786 A|1006 - A|1018 }A1006 - 1018
3X-RAY DIFFRACTION2{ A|787 - A|987 A|1102 - A|1102 }A787 - 987
4X-RAY DIFFRACTION2{ A|787 - A|987 A|1102 - A|1102 }A1102
5X-RAY DIFFRACTION3{ A|988 - A|997 }A988 - 997

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