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- PDB-8sc7: Structure of EGFR in complex with MTX-531 -

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Basic information

Entry
Database: PDB / ID: 8sc7
TitleStructure of EGFR in complex with MTX-531
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/INHIBITOR / EGFR / dual EGFR/PI3K inhibitor / TRANSFERASE / TRANSFERASE-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 / 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 / eyelid development in camera-type eye / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / 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 / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / cellular response to cadmium ion / EGFR Transactivation by Gastrin / positive regulation of DNA repair / 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 / positive regulation of synaptic transmission, glutamatergic / cellular response to dexamethasone stimulus / ossification / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / 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 / lung development / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane / positive regulation of miRNA transcription / cell-cell adhesion
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
: / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.984 Å
AuthorsWhitehead, C.E. / Leopold, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Structure of EGFR in complex with MTX-531
Authors: Whitehead, C.E. / Leopold, J.
History
DepositionApr 5, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release

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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)38,1454
Polymers37,5631
Non-polymers5813
Water3,909217
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.517, 145.517, 145.517
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Components on special symmetry positions
IDModelComponents
11A-1370-

HOH

21A-1414-

HOH

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Components

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


Mass: 37563.457 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-D0D / N-[(5P)-2-chloro-5-(4-{[(1R)-1-phenylethyl]amino}quinazolin-6-yl)pyridin-3-yl]methanesulfonamide


Mass: 453.945 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20ClN5O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 3.42 Å3/Da / Density % sol: 64.01 %
Crystal growTemperature: 285 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 1.05 M Sodium Succinate pH 7.0, 0.1 M HEPES-NaOH pH 6.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.965459 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Oct 29, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.965459 Å / Relative weight: 1
ReflectionResolution: 1.984→34.299 Å / Num. obs: 34279 / % possible obs: 96.6 % / Redundancy: 39.82 %
Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways throughout the data processing steps (rejection of overloaded or too partial reflections, outlier/misfit rejections during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC1/2: 1 / CC1/2 anomalous: -0.372 / Rmerge(I) obs: 0.0874 / Rpim(I) all: 0.0141 / Rrim(I) all: 0.0886 / AbsDiff over sigma anomalous: 0.748 / Aniso diffraction limit 1: 1.984 Å / Aniso diffraction limit 2: 1.984 Å / Aniso diffraction limit 3: 1.984 Å / Aniso diffraction limit axis 1 ortho1: 1 / Aniso diffraction limit axis 1 ortho2: 0 / Aniso diffraction limit axis 1 ortho3: 0 / Aniso diffraction limit axis 2 ortho1: 0 / Aniso diffraction limit axis 2 ortho2: 1 / Aniso diffraction limit axis 2 ortho3: 0 / Aniso diffraction limit axis 3 ortho1: 0 / Aniso diffraction limit axis 3 ortho2: 0 / Aniso diffraction limit axis 3 ortho3: 1 / Net I/σ(I): 29.54 / Num. measured all: 1364986 / Observed signal threshold: 1.2 / Orthogonalization convention: pdb / % possible anomalous: 96.6 / % possible ellipsoidal: 96.6 / % possible ellipsoidal anomalous: 96.6 / % possible spherical: 96.6 / % possible spherical anomalous: 96.6 / Redundancy anomalous: 20.54 / Signal type: local
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
4.376-34.29935.430.039194.16121027121027341634160.999-0.3960.00650.03960.77910010010010010018.97100
3.459-4.37638.120.04880.41131526131526345034500.999-0.4640.00780.04870.7410010010010010019.81100
3.015-3.45941.190.083451.87141112141112342634260.998-0.4020.01320.08440.75410010010010010021.3100
2.733-3.01536.960.158628.5126102126102341234120.997-0.1250.02630.16080.75710010010010010019.05100
2.537-2.73339.440.305816.6135679135679344034400.992-0.0490.04920.30980.75910010010010010020.26100
2.385-2.53741.190.54619.47141174141174342734270.98-0.0220.08590.55290.7410010010010010021.11100
2.264-2.38541.840.836.17143332143332342634260.953-0.0610.12950.84010.72610010010010010021.42100
2.165-2.26441.931.2384.16143689143689342734270.901-0.0570.19311.25310.7310010010010010021.45100
2.08-2.16542.51.96342.53145978145978343534350.802-0.0070.30411.9870.72810010010010010021.71100
1.984-2.0839.583.32561.45135367135367342034200.588-0.010.53393.36840.76774.574.174.574.174.520.1574.1

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Processing

Software
NameVersionClassification
autoPROC1.1.7 20220608data processing
XDSJan 10, 2022data reduction
Aimless0.7.9data scaling
STARANISO2.3.87data scaling
REFMAC5.8.0352refinement
REFMAC5.8.0352phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.984→34.299 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.956 / SU B: 7.143 / SU ML: 0.099 / Cross valid method: FREE R-VALUE / ESU R: 0.141 / ESU R Free: 0.131
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2156 1439 4.199 %
Rwork0.1859 32835 -
all0.187 --
obs-34274 96.538 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 57.55 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.984→34.299 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2606 0 38 217 2861
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0122771
X-RAY DIFFRACTIONr_bond_other_d0.0020.0162593
X-RAY DIFFRACTIONr_ext_dist_refined_b00.013760
X-RAY DIFFRACTIONr_angle_refined_deg1.3151.6723766
X-RAY DIFFRACTIONr_angle_other_deg0.4741.5786049
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5665337
X-RAY DIFFRACTIONr_dihedral_angle_2_deg3.941518
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.72210501
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.78110119
X-RAY DIFFRACTIONr_chiral_restr0.0620.2413
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023255
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02533
X-RAY DIFFRACTIONr_nbd_refined0.2090.2493
X-RAY DIFFRACTIONr_symmetry_nbd_other0.180.22496
X-RAY DIFFRACTIONr_nbtor_refined0.1680.21340
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0720.21384
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1430.2141
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0030.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2150.222
X-RAY DIFFRACTIONr_nbd_other0.1490.289
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1870.221
X-RAY DIFFRACTIONr_mcbond_it2.1775.1871331
X-RAY DIFFRACTIONr_mcbond_other2.1765.1871331
X-RAY DIFFRACTIONr_mcangle_it3.7127.7591673
X-RAY DIFFRACTIONr_mcangle_other3.7117.7621674
X-RAY DIFFRACTIONr_scbond_it2.0295.41440
X-RAY DIFFRACTIONr_scbond_other2.0285.3991441
X-RAY DIFFRACTIONr_scangle_it3.4587.9832093
X-RAY DIFFRACTIONr_scangle_other3.4577.9822094
X-RAY DIFFRACTIONr_lrange_it7.07898.9655599
X-RAY DIFFRACTIONr_lrange_other7.06398.3525559
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.984-2.0360.254660.3311384X-RAY DIFFRACTION55.7692
2.036-2.0910.2881060.2872360X-RAY DIFFRACTION97.2781
2.091-2.1520.2481090.2422371X-RAY DIFFRACTION100
2.152-2.2180.2741010.2232275X-RAY DIFFRACTION100
2.218-2.290.264930.222234X-RAY DIFFRACTION100
2.29-2.370.233830.2112155X-RAY DIFFRACTION100
2.37-2.4590.256990.2042069X-RAY DIFFRACTION100
2.459-2.5590.199870.2022005X-RAY DIFFRACTION100
2.559-2.6720.231730.1961936X-RAY DIFFRACTION100
2.672-2.8020.195810.2011831X-RAY DIFFRACTION100
2.802-2.9520.231640.1851766X-RAY DIFFRACTION100
2.952-3.130.244780.1891665X-RAY DIFFRACTION100
3.13-3.3440.194680.1831552X-RAY DIFFRACTION100
3.344-3.6090.214700.1851458X-RAY DIFFRACTION100
3.609-3.9490.206610.1741349X-RAY DIFFRACTION100
3.949-4.4080.204550.1551221X-RAY DIFFRACTION100
4.408-5.0760.17530.1511081X-RAY DIFFRACTION100
5.076-6.1830.257470.204929X-RAY DIFFRACTION100
6.183-8.6050.22260.187747X-RAY DIFFRACTION100
8.605-34.2990.18190.173447X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 24.8463 Å / Origin y: 7.3736 Å / Origin z: 58.2865 Å
111213212223313233
T0.0655 Å20.0194 Å20.0373 Å2-0.08 Å2-0.0171 Å2--0.0447 Å2
L1.0021 °2-0.9052 °2-0.3673 °2-1.6063 °20.5477 °2--0.3035 °2
S0.1841 Å °0.2407 Å °0.0178 Å °-0.2033 Å °-0.2013 Å °-0.0944 Å °-0.0239 Å °-0.133 Å °0.0172 Å °
Refinement TLS groupSelection: ALL

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