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- PDB-7lgs: Structure of EGFR_D770_N771insNPG/V948R in complex with covalent ... -

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Basic information

Entry
Database: PDB / ID: 7lgs
TitleStructure of EGFR_D770_N771insNPG/V948R in complex with covalent inhibitor Osimertinib.
ComponentsEpidermal growth factor receptor
KeywordsHYDROLASE/HYDROLASE inhibitor / Kinase / inhibitor / covalent / HYDROLASE / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / 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 prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / 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 / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / regulation of nitric-oxide synthase activity / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of DNA repair / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / neurogenesis / cellular response to dexamethasone stimulus / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / clathrin-coated endocytic vesicle membrane / lung development / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / 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 / 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
CITRIC ACID / Chem-Q6K / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsSkene, R.J. / Lane, W.
CitationJournal: Cancer Discov / Year: 2021
Title: Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer.
Authors: Gonzalvez, F. / Vincent, S. / Baker, T.E. / Gould, A.E. / Li, S. / Wardwell, S.D. / Nadworny, S. / Ning, Y. / Zhang, S. / Huang, W.S. / Hu, Y. / Li, F. / Greenfield, M.T. / Zech, S.G. / Das, ...Authors: Gonzalvez, F. / Vincent, S. / Baker, T.E. / Gould, A.E. / Li, S. / Wardwell, S.D. / Nadworny, S. / Ning, Y. / Zhang, S. / Huang, W.S. / Hu, Y. / Li, F. / Greenfield, M.T. / Zech, S.G. / Das, B. / Narasimhan, N.I. / Clackson, T. / Dalgarno, D. / Shakespeare, W.C. / Fitzgerald, M. / Chouitar, J. / Griffin, R.J. / Liu, S. / Wong, K.K. / Zhu, X. / Rivera, V.M.
History
DepositionJan 21, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: 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
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)153,32115
Polymers150,7504
Non-polymers2,57111
Water2,756153
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2513
Polymers37,6881
Non-polymers5642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6307
Polymers37,6881
Non-polymers9426
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2513
Polymers37,6881
Non-polymers5642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1892
Polymers37,6881
Non-polymers5021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)60.659, 132.100, 85.805
Angle α, β, γ (deg.)90.000, 91.400, 90.000
Int Tables number4
Space group name H-MP1211

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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.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Baculoviridae sp. (virus)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-Q6K / ~{N}-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide


Mass: 501.623 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H35N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-CIT / CITRIC ACID / Citric acid


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 153 / 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: 2.28 Å3/Da / Density % sol: 46.05 %
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: 5.0.3 / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: May 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.94→49.01 Å / Num. obs: 28583 / % possible obs: 99.3 % / Redundancy: 3.8 % / CC1/2: 0.989 / Rmerge(I) obs: 0.269 / Rpim(I) all: 0.16 / Rrim(I) all: 0.313 / Net I/σ(I): 4
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
2.94-3.123.82.0731756645920.4091.2272.4120.899.1
8.82-46.923.70.045400010910.9980.0270.05216.298.7

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Processing

Software
NameVersionClassification
Aimless0.7.3data scaling
REFMAC5.8.0257refinement
PDB_EXTRACT3.27data extraction
DENZOdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LRM

4lrm


Resolution: 3.1→49.01 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.874 / SU B: 40.894 / SU ML: 0.654 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.641 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3053 1148 4.9 %RANDOM
Rwork0.2377 ---
obs0.241 22057 94.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 159.15 Å2 / Biso mean: 84.016 Å2 / Biso min: 14.08 Å2
Baniso -1Baniso -2Baniso -3
1-6.76 Å2-0 Å2-3.32 Å2
2---2.95 Å20 Å2
3----3.63 Å2
Refinement stepCycle: final / Resolution: 3.1→49.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9049 0 185 153 9387
Biso mean--80.51 51.53 -
Num. residues----1131
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0129452
X-RAY DIFFRACTIONr_angle_refined_deg0.8921.65812773
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2751125
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.19221.923442
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.11151723
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2831558
X-RAY DIFFRACTIONr_chiral_restr0.070.21201
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.027202
LS refinement shellResolution: 3.1→3.179 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.413 56 -
Rwork0.346 1197 -
obs--68.51 %

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