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- PDB-7t4j: Crystal Structure of EGFR_D770_N771insNPG/V948R in complex with T... -

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Basic information

Entry
Database: PDB / ID: 7t4j
TitleCrystal Structure of EGFR_D770_N771insNPG/V948R in complex with TAK-788
ComponentsEpidermal growth factor receptor
KeywordsHYDROLASE/HYDROLASE Inhibitor / Kinase / Inhibitor / covalent / HYDROLASE / HYDROLASE-HYDROLASE 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / 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 / 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 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / ossification / SHC1 events in ERBB2 signaling / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / EGFR downregulation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / cell-cell adhesion / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / neuron differentiation / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Cargo recognition for clathrin-mediated endocytosis / PIP3 activates AKT signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / virus receptor activity / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / 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 / positive regulation of ERK1 and ERK2 cascade
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
CITRIC ACID / Chem-R28 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsSkene, R.J. / Lane, W. / Hu, Y.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non-small cell lung cancer.
Authors: Huang, W.S. / Li, F. / Gong, Y. / Zhang, Y. / Youngsaye, W. / Xu, Y. / Zhu, X. / Greenfield, M.T. / Kohlmann, A. / Taslimi, P.M. / Toms, A. / Zech, S.G. / Zhou, T. / Das, B. / Jang, H.G. / ...Authors: Huang, W.S. / Li, F. / Gong, Y. / Zhang, Y. / Youngsaye, W. / Xu, Y. / Zhu, X. / Greenfield, M.T. / Kohlmann, A. / Taslimi, P.M. / Toms, A. / Zech, S.G. / Zhou, T. / Das, B. / Jang, H.G. / Tugnait, M. / Ye, Y.E. / Gonzalvez, F. / Baker, T.E. / Nadworny, S. / Ning, Y. / Wardwell, S.D. / Zhang, S. / Gould, A.E. / Hu, Y. / Lane, W. / Skene, R.J. / Zou, H. / Clackson, T. / Narasimhan, N.I. / Rivera, V.M. / Dalgarno, D.C. / Shakespeare, W.C.
History
DepositionDec 10, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 7, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)76,9977
Polymers75,3752
Non-polymers1,6225
Water1,71195
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.121, 85.531, 127.854
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Components on special symmetry positions
IDModelComponents
11B-1238-

HOH

21B-1239-

HOH

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Components

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


Mass: 37687.520 Da / Num. of mol.: 2 / Mutation: V948R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-R28 / propan-2-yl 2-[[4-[2-(dimethylamino)ethyl-methyl-amino]-2-methoxy-5-(propanoylamino)phenyl]amino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate / Mobocertinib, bound form


Mass: 587.712 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H41N7O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H8O7
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.11 Å3/Da / Density % sol: 41.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 20% PEG 8000, 200mM Ammonium Citrate, 100mM MES pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 27, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.2→48.12 Å / Num. obs: 33163 / % possible obs: 100 % / Redundancy: 7.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.04 / Rrim(I) all: 0.108 / Net I/σ(I): 12
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.2-2.277.23.0742027728240.5041.2223.3130.7100
9.07-48.0760.025333855910.0110.02858.399.5

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0257refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7LGS

7lgs


Resolution: 2.2→48.12 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.942 / SU B: 28.851 / SU ML: 0.301 / SU R Cruickshank DPI: 0.3055 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.306 / ESU R Free: 0.24 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2775 1689 5.1 %RANDOM
Rwork0.2244 ---
obs0.2271 31388 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 181.03 Å2 / Biso mean: 76.126 Å2 / Biso min: 35.28 Å2
Baniso -1Baniso -2Baniso -3
1--1.79 Å2-0 Å20 Å2
2--2.27 Å2-0 Å2
3----0.48 Å2
Refinement stepCycle: final / Resolution: 2.2→48.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4470 0 116 95 4681
Biso mean--80.13 92.06 -
Num. residues----557
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0124688
X-RAY DIFFRACTIONr_angle_refined_deg1.5151.6616337
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6145552
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.98121.946221
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.91315854
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0541529
X-RAY DIFFRACTIONr_chiral_restr0.1090.2590
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023582
LS refinement shellResolution: 2.2→2.257 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.41 120 -
Rwork0.418 2255 -
all-2375 -
obs--98.51 %
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)
10.4437-0.3880.01981.9434-0.22671.3415-0.11130.152-0.00110.44740.0616-0.0854-0.19760.1120.04970.8212-0.0463-0.08390.09060.02890.6687-1.607-37.7415.661
20.7829-0.1390.17783.5672-1.03291.54680.0392-0.03190.0341-0.3957-0.126-0.08520.21120.18510.08690.65730.06450.0550.13260.02050.494224.569-36.59446.118
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A701 - 790
2X-RAY DIFFRACTION1A791 - 987
3X-RAY DIFFRACTION1A1101
4X-RAY DIFFRACTION2B701 - 790
5X-RAY DIFFRACTION2B791 - 987
6X-RAY DIFFRACTION2B1101

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