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- PDB-8hv3: Crystal structure of EGFR_DMX in complex with covalently bound fr... -

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Basic information

Entry
Database: PDB / ID: 8hv3
TitleCrystal structure of EGFR_DMX in complex with covalently bound fragment 4
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / Epidermal growth factor receptor kinase / covalent fragments / mutant EGFR / anti-cancer
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 / ERBB2 Activates PTK6 Signaling / morphogenesis of an epithelial fold / intracellular vesicle / Signaling by EGFR / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / : / 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 glial cell proliferation / positive regulation of phosphorylation / 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 / EGFR Transactivation by Gastrin / positive regulation of DNA repair / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / epithelial cell proliferation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / liver regeneration / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / positive regulation of smooth muscle cell proliferation / lung development / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity / 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 / cell-cell adhesion / Downregulation of ERBB2 signaling / ruffle membrane / cellular response to reactive oxygen species
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
~{N}-pyridin-2-ylprop-2-enamide / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsDokurno, P.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Rsc Med Chem / Year: 2023
Title: A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.
Authors: Kuki, N. / Walmsley, D.L. / Kanai, K. / Takechi, S. / Yoshida, M. / Murakami, R. / Takano, K. / Tominaga, Y. / Takahashi, M. / Ito, S. / Nakao, N. / Angove, H. / Baker, L.M. / Carter, E. / ...Authors: Kuki, N. / Walmsley, D.L. / Kanai, K. / Takechi, S. / Yoshida, M. / Murakami, R. / Takano, K. / Tominaga, Y. / Takahashi, M. / Ito, S. / Nakao, N. / Angove, H. / Baker, L.M. / Carter, E. / Dokurno, P. / Le Strat, L. / Macias, A.T. / Molyneaux, C.A. / Murray, J.B. / Surgenor, A.E. / Hamada, T. / Hubbard, R.E.
History
DepositionDec 26, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID / _citation_author.name

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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)38,1744
Polymers37,5491
Non-polymers6253
Water2,414134
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.040, 145.040, 145.040
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23
Components on special symmetry positions
IDModelComponents
11A-1332-

HOH

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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-PE5 / 3,6,9,12,15,18,21,24-OCTAOXAHEXACOSAN-1-OL / 2-(2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHANOL / POLYETHYLENE GLYCOL PEG400 / Polyethylene glycol


Mass: 398.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H38O9 / Comment: precipitant*YM
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-MWU / ~{N}-pyridin-2-ylprop-2-enamide


Mass: 148.162 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H8N2O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 134 / 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: 3.39 Å3/Da / Density % sol: 63.67 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1M TRIS pH 8.5, 0.15M Sodium citrate, 25%PEG400

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Data collection

DiffractionMean temperature: 110 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER TURBO X-RAY SOURCE / Wavelength: 1.54184 Å
DetectorType: BRUKER PHOTON 100 / Detector: CMOS / Date: Jan 24, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54184 Å / Relative weight: 1
ReflectionResolution: 2.3→21.87 Å / Num. obs: 22648 / % possible obs: 99.8 % / Redundancy: 7.05 % / Rmerge(I) obs: 0.1621 / Net I/σ(I): 9.3
Reflection shellResolution: 2.3→2.4 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.8204 / Mean I/σ(I) obs: 1.35 / Num. unique obs: 2698 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
SADABSdata scaling
SAINTdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EDQ

5edq


Resolution: 2.4→20 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.932 / SU B: 8.193 / SU ML: 0.183 / Cross valid method: THROUGHOUT / ESU R: 0.282 / ESU R Free: 0.225 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24993 977 4.9 %RANDOM
Rwork0.21202 ---
obs0.21393 18888 99.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 44.518 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 2.4→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2381 0 41 134 2556
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132469
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172396
X-RAY DIFFRACTIONr_angle_refined_deg1.6621.6373336
X-RAY DIFFRACTIONr_angle_other_deg1.2881.5785510
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4165304
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.03522.301113
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.61415423
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0071514
X-RAY DIFFRACTIONr_chiral_restr0.0730.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022708
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02519
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.7954.8191225
X-RAY DIFFRACTIONr_mcbond_other4.7854.8171224
X-RAY DIFFRACTIONr_mcangle_it7.5527.1961526
X-RAY DIFFRACTIONr_mcangle_other7.5517.1991527
X-RAY DIFFRACTIONr_scbond_it4.7494.7551244
X-RAY DIFFRACTIONr_scbond_other4.7474.7561245
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.5176.9941811
X-RAY DIFFRACTIONr_long_range_B_refined13.15483.9711068
X-RAY DIFFRACTIONr_long_range_B_other13.15383.96611069
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.528 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.305 158 -
Rwork0.292 2683 -
obs--100 %

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