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- PDB-5em6: EGFR kinase domain mutant "TMLR" with pyridone compound 19: 4-[(2... -

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Basic information

Entry
Database: PDB / ID: 5em6
TitleEGFR kinase domain mutant "TMLR" with pyridone compound 19: 4-[(2-azanylpyrimidin-4-yl)amino]-~{N}-[4-(4-methylpiperazin-1-yl)phenyl]-2-oxidanylidene-1~{H}-pyridine-3-carboxamide
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 / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / 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 / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / 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 / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / 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 / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / 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 / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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-5Q3 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.78 Å
AuthorsEigenbrot, C. / Yu, C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR.
Authors: Bryan, M.C. / Burdick, D.J. / Chan, B.K. / Chen, Y. / Clausen, S. / Dotson, J. / Eigenbrot, C. / Elliott, R. / Hanan, E.J. / Heald, R. / Jackson, P. / La, H. / Lainchbury, M. / Malek, S. / ...Authors: Bryan, M.C. / Burdick, D.J. / Chan, B.K. / Chen, Y. / Clausen, S. / Dotson, J. / Eigenbrot, C. / Elliott, R. / Hanan, E.J. / Heald, R. / Jackson, P. / La, H. / Lainchbury, M. / Malek, S. / Mann, S.E. / Purkey, H.E. / Schaefer, G. / Schmidt, S. / Seward, E. / Sideris, S. / Wang, S. / Yen, I. / Yu, C. / Heffron, T.P.
History
DepositionNov 5, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 30, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 10, 2016Group: Database references
Revision 1.2Sep 6, 2017Group: Data collection / Derived calculations / Category: diffrn_detector / pdbx_struct_oper_list
Item: _diffrn_detector.detector / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0663
Polymers37,5491
Non-polymers5172
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area190 Å2
ΔGint-14 kcal/mol
Surface area15220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.249, 146.249, 146.249
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,E865A,E866A,K867A
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-5Q3 / 4-[(2-azanylpyrimidin-4-yl)amino]-~{N}-[4-(4-methylpiperazin-1-yl)phenyl]-2-oxidanylidene-1~{H}-pyridine-3-carboxamide


Mass: 420.468 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24N8O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 3.47 Å3/Da / Density % sol: 64.56 %
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: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 4, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.78→59.7 Å / Num. all: 13262 / Num. obs: 13262 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 11.8 % / Biso Wilson estimate: 63.71 Å2 / Rsym value: 0.106 / Net I/σ(I): 28.6
Reflection shellResolution: 2.78→2.88 Å / Redundancy: 12 % / Rmerge(I) obs: 0.487 / Mean I/σ(I) obs: 5.6 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementResolution: 2.78→59.7 Å / Cor.coef. Fo:Fc: 0.9264 / Cor.coef. Fo:Fc free: 0.9095 / SU R Cruickshank DPI: 0.459 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.433 / SU Rfree Blow DPI: 0.266 / SU Rfree Cruickshank DPI: 0.273
RfactorNum. reflection% reflectionSelection details
Rfree0.229 568 4.28 %RANDOM
Rwork0.1947 ---
obs0.1962 13262 99.98 %-
Displacement parametersBiso mean: 50.75 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.377 Å
Refinement stepCycle: 1 / Resolution: 2.78→59.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2422 0 36 6 2464
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092513HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.043403HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d879SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes59HARMONIC2
X-RAY DIFFRACTIONt_gen_planes353HARMONIC5
X-RAY DIFFRACTIONt_it2513HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.53
X-RAY DIFFRACTIONt_other_torsion18.8
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion323SEMIHARMONIC5
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_contact2825SEMIHARMONIC4
LS refinement shellResolution: 2.78→3 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2575 107 3.96 %
Rwork0.2075 2597 -
all0.2095 2704 -
obs--99.98 %
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)
11.12870.4542-1.13930.18390.41024.8438-0.0282-0.00030.0782-0.0481-0.0195-0.0338-0.020.38040.0476-0.0077-0.0970.0131-0.06110.0458-0.059-55.09277.8256-30.0169
21.68870.9524-0.75163.8118-0.5811.7508-0.1405-0.0707-0.202-0.2-0.0631-0.39170.13220.27110.2035-0.0796-0.03220.0727-0.07530.0312-0.1285-60.9382-15.7546-21.9123
30.3378-0.3978-0.44890.18730.07140.2677-0.0019-0.02660.01630.01320.00040.0065-0.0156-0.0150.00140.0358-0.0484-0.01130.03220.0348-0.0253-64.6854.3344-7.2855
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|697 - A|786 A|1004 - A|1019 }A697 - 786
2X-RAY DIFFRACTION1{ A|697 - A|786 A|1004 - A|1019 }A1004 - 1019
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|998 }A988 - 998

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