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- PDB-8h7x: Crystal structure of EGFR T790M/C797S mutant in complex with brig... -

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Basic information

Entry
Database: PDB / ID: 8h7x
TitleCrystal structure of EGFR T790M/C797S mutant in complex with brigatinib
ComponentsEpidermal growth factor receptor
KeywordsSIGNALING PROTEIN / Inhibitor / Complex / Protein Kinase
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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / ubiquitin-dependent endocytosis / PLCG1 events in ERBB2 signaling / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / ERBB2-EGFR signaling pathway / Signaling by EGFR / eyelid development in camera-type eye / intracellular vesicle / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / protein insertion into membrane / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / negative regulation of epidermal growth factor receptor signaling pathway / PI3K events in ERBB2 signaling / positive regulation of peptidyl-serine phosphorylation / hair follicle development / positive regulation of phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / embryonic placenta development / GAB1 signalosome / salivary gland morphogenesis / xenobiotic transport / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / epithelial cell proliferation / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of DNA replication / positive regulation of epithelial cell proliferation / positive regulation of DNA repair / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / cellular response to estradiol stimulus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / sperm end piece / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / cell-cell adhesion / Signaling by ERBB2 ECD mutants / negative regulation of protein catabolic process / Signaling by ERBB2 KD Mutants / positive regulation of protein phosphorylation / positive regulation of miRNA transcription / positive regulation of fibroblast proliferation / cell morphogenesis / epidermal growth factor receptor signaling pathway / ruffle membrane / Downregulation of ERBB2 signaling / kinase binding / Constitutive Signaling by Aberrant PI3K in Cancer / neuron differentiation / HCMV Early Events / actin filament binding / cell junction / transmembrane signaling receptor activity / PIP3 activates AKT signaling / positive regulation of canonical Wnt signaling pathway / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / sperm principal piece / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / double-stranded DNA binding / sperm midpiece / early 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-6GY / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.404 Å
AuthorsKukimoto-Niino, M. / Shirouzu, M.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED) Japan
CitationJournal: NPJ Precis Oncol / Year: 2024
Title: A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer.
Authors: Suzuki, M. / Uchibori, K. / Oh-Hara, T. / Nomura, Y. / Suzuki, R. / Takemoto, A. / Araki, M. / Matsumoto, S. / Sagae, Y. / Kukimoto-Niino, M. / Kawase, Y. / Shirouzu, M. / Okuno, Y. / ...Authors: Suzuki, M. / Uchibori, K. / Oh-Hara, T. / Nomura, Y. / Suzuki, R. / Takemoto, A. / Araki, M. / Matsumoto, S. / Sagae, Y. / Kukimoto-Niino, M. / Kawase, Y. / Shirouzu, M. / Okuno, Y. / Nishio, M. / Fujita, N. / Katayama, R.
History
DepositionOct 21, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 25, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 4, 2026Group: Refinement description / Structure summary
Category: pdbx_entry_details / pdbx_initial_refinement_model
Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,7393
Polymers75,1552
Non-polymers5841
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2050 Å2
ΔGint-13 kcal/mol
Surface area27320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.100, 90.110, 165.310
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 37577.480 Da / Num. of mol.: 2 / Mutation: T790M, C797S
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-6GY / 5-chloro-N~4~-[2-(dimethylphosphoryl)phenyl]-N~2~-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine / Brigatinib


Mass: 584.092 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H39ClN7O2P / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.48 Å3/Da / Density % sol: 50.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.2M sodium tartrate dibasic dihydrate, 22% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL26B2 / Wavelength: 1 Å
DetectorType: RAYONIX MX225-HS / Detector: CCD / Date: Jul 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.4→47.95 Å / Num. obs: 10814 / % possible obs: 99.9 % / Redundancy: 7.2 % / CC1/2: 0.996 / Net I/σ(I): 11.2
Reflection shellResolution: 3.4→3.61 Å / Redundancy: 7.3 % / Num. unique obs: 1729 / CC1/2: 0.764 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5XGN

5xgn


Resolution: 3.404→47.946 Å / SU ML: 0.47 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 28.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2557 1082 10.01 %
Rwork0.1811 9732 -
obs0.1889 10814 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 220.05 Å2 / Biso mean: 103.5682 Å2 / Biso min: 50.54 Å2
Refinement stepCycle: final / Resolution: 3.404→47.946 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4768 0 40 0 4808
Biso mean--95.48 --
Num. residues----603
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.404-3.55890.36841340.3051201100
3.5589-3.74640.36841300.24981176100
3.7464-3.98110.30011330.2125118799
3.9811-4.28830.25491340.18761206100
4.2883-4.71950.21161340.13571198100
4.7195-5.40160.21511340.14771213100
5.4016-6.80230.25991370.17861230100
6.8023-100.22951460.16461321100
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)
11.22282.08960.13064.76710.45763.3146-0.16190.06630.1778-0.1710.09630.0825-0.11880.1628-0.02950.8542-0.0346-0.11790.82240.10160.75745.203121.3461186.1677
23.44050.01272.18252.0958-0.78375.6223-0.3084-0.03830.0411-0.07530.1662-0.0649-0.1410.02040.15060.58630.08980.09650.6143-0.03420.699713.434614.2584206.959
36.6235-2.7862-2.01294.85091.29493.99640.78361.39480.3524-0.4345-1.13940.3959-0.168-0.23690.17810.85330.25020.10980.93250.08750.9313-7.3533-3.1537144.0223
42.8719-2.7739-0.9764.02142.87074.87520.64431.36560.2619-0.3899-0.09061.08710.6645-0.7589-0.52321.053-0.0311-0.16660.88610.08090.9082-9.6915-2.3166142.1318
50.9804-0.2416-0.04653.88322.14126.9520.11920.0168-0.06960.2902-0.2520.39940.6862-0.17620.22720.6225-0.08790.00970.5170.08810.7713-4.5674-2.1631157.852
62.2113-1.7551-2.68911.51342.13283.26161.07990.17440.2041-0.8818-0.55630.031-0.69330.8122-0.43170.92470.14380.14510.81440.16850.69915.36798.5484156.4746
72.1282-0.01580.35222.96040.46486.64480.1956-0.21590.26290.1476-0.1243-0.048-0.20290.1239-0.05130.5081-0.0969-0.00950.51130.08190.7541-3.84466.0841170.3938
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 697 through 768 )A697 - 768
2X-RAY DIFFRACTION2chain 'A' and (resid 769 through 1019 )A769 - 1019
3X-RAY DIFFRACTION3chain 'B' and (resid 697 through 732 )B697 - 732
4X-RAY DIFFRACTION4chain 'B' and (resid 733 through 752 )B733 - 752
5X-RAY DIFFRACTION5chain 'B' and (resid 753 through 853 )B753 - 853
6X-RAY DIFFRACTION6chain 'B' and (resid 854 through 882 )B854 - 882
7X-RAY DIFFRACTION7chain 'B' and (resid 883 through 1018 )B883 - 1018

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