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- PDB-7zym: Crystal Structure of EGFR-T790M/C797S in Complex with Brigatinib -

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Basic information

Entry
Database: PDB / ID: 7zym
TitleCrystal Structure of EGFR-T790M/C797S in Complex with Brigatinib
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M/C797S / inhibitor
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / 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 / hydrogen peroxide metabolic process / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / protein tyrosine kinase activator activity / response to cobalamin / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / 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 / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of vasoconstriction / positive regulation of glial cell proliferation / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / ossification / cellular response to dexamethasone stimulus / neurogenesis / positive regulation of synaptic transmission, glutamatergic / positive regulation of epithelial cell proliferation / neuron projection morphogenesis / basal plasma membrane / epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / lung development / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of smooth muscle cell proliferation / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / kinase binding / Downregulation of ERBB2 signaling / positive regulation of miRNA transcription / cell-cell adhesion / peptidyl-tyrosine phosphorylation / ruffle 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 / 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: 2.5 Å
AuthorsNiggenaber, J. / Kleinboelting, S. / Mueller, M.P. / Rauh, D.
Funding support Germany, European Union, 3items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and ResearchBMBF 01ZX1303C Germany
European Regional Development FundEFRE-800400European Union
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines.
Authors: Grabe, T. / Jeyakumar, K. / Niggenaber, J. / Schulz, T. / Koska, S. / Kleinbolting, S. / Beck, M.E. / Muller, M.P. / Rauh, D.
History
DepositionMay 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Structure summary / Category: audit_author
Revision 1.2May 31, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)38,3002
Polymers37,7161
Non-polymers5841
Water39622
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.100, 146.100, 146.100
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Space group name HallI223

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Components

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


Mass: 37715.613 Da / Num. of mol.: 1
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 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.45 Å3/Da / Density % sol: 64.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.4 K-Na-tartrate, 100 mM Na-MES (pH 6.5), 3.5 mg/mL EGFR-WT (in 100 mM NaCl, 25 mM Tris-HCl, 10 % glycerol, 1 mM TCEP) pH 8.0) 1 ul reservoir + 1 ul solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.915 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 24, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.915 Å / Relative weight: 1
ReflectionResolution: 2.5→42.18 Å / Num. obs: 18104 / % possible obs: 100 % / Redundancy: 19.66 % / Biso Wilson estimate: 62.79 Å2 / CC1/2: 0.996 / Rrim(I) all: 0.166 / Net I/σ(I): 12.51
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 19.47 % / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1985 / CC1/2: 0.773 / Rrim(I) all: 1.464 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6S89

6s89


Resolution: 2.5→42.18 Å / SU ML: 0.3084 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.2217
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2237 906 5.01 %
Rwork0.1923 17190 -
obs0.1939 18096 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 70.43 Å2
Refinement stepCycle: LAST / Resolution: 2.5→42.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2486 0 40 22 2548
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00252587
X-RAY DIFFRACTIONf_angle_d0.56143520
X-RAY DIFFRACTIONf_chiral_restr0.0441394
X-RAY DIFFRACTIONf_plane_restr0.0046442
X-RAY DIFFRACTIONf_dihedral_angle_d15.9467949
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.660.30621500.27382849X-RAY DIFFRACTION99.93
2.66-2.860.32881500.28762841X-RAY DIFFRACTION99.97
2.86-3.150.27791480.2452820X-RAY DIFFRACTION100
3.15-3.610.2451510.22962857X-RAY DIFFRACTION100
3.61-4.540.19351510.17042864X-RAY DIFFRACTION100
4.54-42.180.19211560.15362959X-RAY DIFFRACTION99.87
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)
15.41749039761.410594867693.474729448721.275498857621.102247752465.691254602830.089093483557-0.065940947516-0.0298020592751-0.206482624517-0.0184413988512-0.301129329809-0.678780111869-0.360521345558-0.1042382732890.563555567591-0.04816756859120.05282538986430.5784231825750.05179720997440.518973360043-56.02619631459.49435286252-34.0549172689
27.86993089421-0.631770998222-0.7474727987475.254618570122.324355362965.516399496180.177465268453-0.025462610870.4309714346140.2704377082220.154884427988-0.954680990268-0.190536149520.729985153711-0.3221893960430.580850088019-0.137330482874-0.02025352484670.5872951254260.04098269614920.498290709792-51.69596176998.80652851782-24.9159972977
33.829166587822.53913730543-1.193444112415.90541582981-0.9313458807344.373126288960.259795037332-0.0290612630077-0.388740360790.127929352115-0.194600611896-0.602142995736-0.2006312117150.573727455429-0.1969299817530.61237348309-0.02765131351080.001712765705360.6474868524130.08377361778070.548856576689-54.93779680251.78020953344-34.739542853
42.874655537791.30363377308-1.477880892086.26657908727-2.236215143362.121045421720.388097796407-0.345935523461-0.05088620714821.14242138236-0.478447923116-0.445568918125-0.3756181790440.3839148318280.1056101361270.741754680076-0.17193462252-0.1273284322610.608807791810.04470453323080.425450588397-56.4473735258-3.49247252498-14.9746455372
53.639358681161.20162091674-1.061317663754.95776032365-1.355663407922.404241128530.05889115839460.06784723538510.007608229439640.101578872316-0.179871284975-0.181183821069-0.1165623035610.1672976144250.01674502284650.442940898966-0.0136453066267-0.03008846990320.3732489660850.02277831559950.324866090606-64.1864269768-8.71507207334-23.4320149271
67.609920049583.159601529254.150397441293.63521919025.331922398538.92177554654-0.3497365580880.395936461871-0.397279637122-0.5702052954310.168666623136-0.324223172163-0.3118906207190.4020661228440.344227130120.786598663339-0.006779239095340.04936506513190.7841225361710.07639906601650.640881895421-57.0297705788-12.9891646918-39.1483756483
72.96545602478-0.117845665051-1.513931126634.84562632616-0.8842235214275.39251035167-0.1562298461970.100270051874-0.254352504281-0.404805982536-0.279791762201-0.6824899373240.3265176681710.5295367926820.3543165057390.4612491782620.01216816319520.05360799718460.4296150406880.0927499321650.477145825836-57.811875918-23.8558589182-23.8392900802
88.749422706480.2126810204750.6141302685975.89030366004-1.761862762660.534073916865-0.203289388252-0.4976445928430.1829152826430.6346520884350.07405088091820.338002210017-0.848144296658-0.9167709955460.2294223412620.615728260756-0.06448969452440.02348731749120.300329684572-0.04764914014340.318696844676-72.7896039525-17.1079598368-13.6847336698
93.74516984504-1.142074423030.6715332575269.374914531222.205200275720.717002736689-0.368387657758-0.625469605790.2149957925291.919919229590.3452932518140.839269766068-1.088600206680.04375786470340.3500682874341.29664380424-0.0829477440974-0.1421335635451.29780090180.1025520059750.891375302383-60.51316699785.87639141055-8.59179690703
109.35816980151-0.133736424002-4.230979366875.958058578350.9762122575494.42881101720.51579785409-0.4346076141420.1430821841060.60336155216-0.0197881168634-0.832144224594-0.377656381740.247420569203-0.2811658241440.858087408935-0.129439982051-0.05037019468460.6605492722490.0371536076470.661432380757-61.820685977614.8908981487-20.8268115553
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 696 through 717 )696 - 7171 - 22
22chain 'A' and (resid 718 through 752 )718 - 75223 - 53
33chain 'A' and (resid 753 through 786 )753 - 78654 - 87
44chain 'A' and (resid 787 through 810 )787 - 81088 - 111
55chain 'A' and (resid 811 through 853 )811 - 853112 - 154
66chain 'A' and (resid 854 through 873 )854 - 873155 - 174
77chain 'A' and (resid 874 through 960 )874 - 960175 - 261
88chain 'A' and (resid 961 through 986 )961 - 986262 - 287
99chain 'A' and (resid 987 through 1002 )987 - 1002288 - 303
1010chain 'A' and (resid 1003 through 1020 )1003 - 1020304 - 321

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