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- PDB-5hcz: EGFR kinase domain mutant "TMLR" with 3-azetidinyl azaindazole co... -

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Basic information

Entry
Database: PDB / ID: 5hcz
TitleEGFR kinase domain mutant "TMLR" with 3-azetidinyl azaindazole compound 21
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of epithelial cell proliferation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway / neuron differentiation / cell morphogenesis / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / Cargo recognition for clathrin-mediated endocytosis / cell junction / transmembrane signaling receptor activity / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / virus receptor activity / ATPase binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / endosome membrane
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-60E / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.62 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)38,1973
Polymers37,5491
Non-polymers6482
Water18010
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area190 Å2
ΔGint-15 kcal/mol
Surface area15430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.449, 146.449, 146.449
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-60E / 2-[1-[1-[(2~{S})-butan-2-yl]-6-[[2-(1-cyclopropylsulfonylpyrazol-4-yl)pyrimidin-4-yl]amino]pyrazolo[4,3-c]pyridin-3-yl]azetidin-3-yl]propan-2-ol


Mass: 551.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H33N9O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 3.49 Å3/Da / Density % sol: 64.71 %
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: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 4, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.62→24.5 Å / Num. all: 15659 / Num. obs: 15659 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5.5 % / Biso Wilson estimate: 72.36 Å2 / Rsym value: 0.052 / Net I/σ(I): 28.3
Reflection shellResolution: 2.62→2.72 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.617 / Mean I/σ(I) obs: 2.6 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EM5

5em5


Resolution: 2.62→23.96 Å / Cor.coef. Fo:Fc: 0.9423 / Cor.coef. Fo:Fc free: 0.9219 / SU R Cruickshank DPI: 0.331 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.315 / SU Rfree Blow DPI: 0.229 / SU Rfree Cruickshank DPI: 0.236
RfactorNum. reflection% reflectionSelection details
Rfree0.2269 653 4.17 %RANDOM
Rwork0.1941 ---
obs0.1955 15659 98.88 %-
Displacement parametersBiso mean: 60.8 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.371 Å
Refinement stepCycle: 1 / Resolution: 2.62→23.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2408 0 44 10 2462
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092509HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.093405HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d876SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes57HARMONIC2
X-RAY DIFFRACTIONt_gen_planes348HARMONIC5
X-RAY DIFFRACTIONt_it2509HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.6
X-RAY DIFFRACTIONt_other_torsion17.7
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion321SEMIHARMONIC5
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_contact2873SEMIHARMONIC4
LS refinement shellResolution: 2.62→2.8 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2138 100 3.61 %
Rwork0.2221 2672 -
all0.2218 2772 -
obs--98.88 %
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)
12.61940.2256-1.00731.29490.15853.73560.0295-0.12860.2071-0.1246-0.0766-0.1742-0.11360.3260.0471-0.066-0.08190.0539-0.05980.0399-0.0409-55.2577.264-30.351
21.6570.5192-0.73623.2905-0.82021.3239-0.0902-0.1054-0.1862-0.1026-0.0764-0.39150.08580.19520.1666-0.0959-0.03840.0488-0.0430.0598-0.1211-61.342-15.884-21.924
30-0.3923-0.50920.1940.1380.4781-0.0044-0.00890.01650.0055-0.00460.0138-0.0146-0.00590.0090.0658-0.00710.00110.00730.021-0.0196-64.8824.338-6.96
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|696 - A|786 A|1006 - A|1019 }A696 - 786
2X-RAY DIFFRACTION1{ A|696 - A|786 A|1006 - A|1019 }A1006 - 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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