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- PDB-6z4d: Crystal Structure of EGFR-T790M/V948R in Complex with Mavelertini... -

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Basic information

Entry
Database: PDB / ID: 6z4d
TitleCrystal Structure of EGFR-T790M/V948R in Complex with Mavelertinib and EAI001
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR
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 / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / eyelid development in camera-type eye / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / activation of phospholipase C activity / positive regulation of cyclin-dependent protein serine/threonine kinase activity / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / 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 / positive regulation of DNA repair / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / 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 / liver regeneration / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / clathrin-coated endocytic vesicle membrane / positive regulation of smooth muscle cell proliferation / lung development / Signaling by ERBB2 TMD/JMD mutants / 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 / cell-cell adhesion / receptor protein-tyrosine kinase / ruffle membrane / Downregulation of ERBB2 signaling / 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
Chem-57N / Chem-8BS / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsNiggenaber, J. / Mueller, M.P. / Rauh, D.
Funding support Germany, 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-800400 Germany
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands.
Authors: Niggenaber, J. / Heyden, L. / Grabe, T. / Muller, M.P. / Lategahn, J. / Rauh, D.
History
DepositionMay 25, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 11, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: 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_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)77,59210
Polymers75,9282
Non-polymers1,6658
Water3,135174
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,5734
Polymers37,9641
Non-polymers6103
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0196
Polymers37,9641
Non-polymers1,0555
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.610, 83.900, 89.270
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 37963.910 Da / Num. of mol.: 2 / Mutation: T790M, V948R
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-8BS / N-[(3R,4R)-4-fluoro-1-{6-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-9-methyl-9H-purin-2-yl}pyrrolidin-3-yl]propanamide


Mass: 417.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24FN9O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-57N / (2R)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2-phenyl-N-(1,3-thiazol-2-yl)acetamide


Mass: 349.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15N3O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 174 / 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 % sol: 34.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 27.5 % PEG3350, 100 mM MgSO4, 2 % ethylen glycole, 5.0 mg/mL EGFR-T790M/V948R (in 100 mM NaCl, 25 mM Tris-HCl, 10 % glycerol, 1 mM TCEP, pH 8.0) 1 ul reservoir + 1 ul protein solution)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Mar 31, 2020
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2→47.79 Å / Num. obs: 39566 / % possible obs: 100 % / Redundancy: 13.44 % / CC1/2: 0.999 / Rrim(I) all: 0.091 / Net I/σ(I): 16.12
Reflection shellResolution: 2→2.1 Å / Redundancy: 13.75 % / Mean I/σ(I) obs: 1.8 / Num. unique obs: 5312 / CC1/2: 0.78 / Rrim(I) all: 1.648 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6S8A

6s8a


Resolution: 2→47.79 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2214 1978 5 %
Rwork0.1931 37574 -
obs0.1945 39552 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 132.88 Å2 / Biso mean: 52.2716 Å2 / Biso min: 27.59 Å2
Refinement stepCycle: final / Resolution: 2→47.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4190 0 110 174 4474
Biso mean--57.77 51.77 -
Num. residues----539
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2-2.050.3751400.313826492789
2.05-2.110.28461390.276826432782
2.11-2.170.28281380.257126222760
2.17-2.240.3051400.239326662806
2.24-2.320.27141390.221126442783
2.32-2.410.28661400.219326772817
2.41-2.520.25081400.225326432783
2.52-2.650.24511400.224126682808
2.65-2.820.25421410.220926722813
2.82-3.040.27331400.220226672807
3.04-3.340.23131430.207727212864
3.34-3.830.18891430.184227102853
3.83-4.820.15521430.147227262869
4.82-47.790.21941520.173828663018
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)
11.65170.16330.91731.56750.87852.4227-0.19130.22660.1494-0.22750.16930.2355-0.16440.23540.00730.4994-0.0841-0.00950.4374-0.05330.4489-40.5271-5.367-6.7992
22.35730.2370.27091.63510.95564.5449-0.14330.42970.392-0.17460.04130.0597-0.5641-0.05270.02660.4685-0.0578-0.06170.40060.08050.4198-41.22641.0679-4.0946
31.7009-0.26050.47930.25050.66382.4111-0.09960.0647-0.1620.0609-0.12750.16020.17180.27320.12070.3365-0.00910.05310.29760.00530.4926-41.9052-9.69685.3358
42.53930.1027-0.97741.80510.14281.8409-0.0845-0.0122-0.2080.0892-0.02560.1357-0.0426-0.14410.08490.33320.01730.0220.29840.03840.3875-51.7315-6.560817.2341
52.6598-1.05461.3630.719-0.73062.1606-0.1203-0.3577-0.04290.72840.0144-0.0935-0.0913-0.0522-0.00430.4320.04570.06830.4270.08160.4052-53.8265-5.363529.5315
61.65270.92820.01460.77310.28211.171-0.1599-0.3423-0.47540.6931-0.0252-0.6440.17560.26040.16830.48640.0406-0.03960.48190.15090.5496-41.5711-14.053229.3972
71.14590.15480.3262.0131-0.22471.11560.0978-0.2708-0.58410.8642-0.15070.5577-0.37130.16690.01440.59880.08310.17540.3595-0.1140.6171-22.2062-21.62146.9665
81.21021.3928-0.75083.4912-1.55282.2861-0.75710.4201-0.90480.59050.53080.94380.0626-0.004-0.11690.50080.16210.210.3608-0.12550.6864-23.238-22.96667.5485
92.60571.6231-1.3137.79654.3234.560.206-1.0234-0.46371.21540.2559-0.64170.5979-0.3074-0.33360.97640.08980.04030.4610.10490.5171-18.7967-19.958221.6152
101.7716-0.3127-0.6072.18430.74391.889-0.02680.108-0.0005-0.03970.04790.18280.07640.17-0.02180.3321-0.00390.02040.3445-0.01070.3035-21.3561-4.6267.1966
112.2368-0.42660.55061.8061-0.30131.6701-0.0006-0.0698-0.32180.0245-0.00470.00160.1126-0.0191-0.06540.32780.02020.01290.4512-0.03950.2936-18.9163-3.739910.8189
120.1157-0.0727-0.21270.36420.70971.30580.4349-0.122-0.24750.3574-0.11-0.07690.36160.8772-0.25350.41460.037-0.03140.8116-0.12390.4427-5.0252-3.268516.6339
131.72060.03331.02231.5709-0.71890.9339-0.01580.21250.0849-0.06920.008-0.2008-0.40911.6480.01640.3502-0.08290.04410.7324-0.00260.3276-8.00264.47348.5888
141.7680.3572-0.23942.4303-0.12864.3021-0.0836-0.06750.5190.1178-0.0126-0.0883-0.98950.9429-0.00730.4839-0.23420.04450.4693-0.03250.3949-11.579613.003510.6338
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 701 through 731 )A701 - 731
2X-RAY DIFFRACTION2chain 'A' and (resid 732 through 768 )A732 - 768
3X-RAY DIFFRACTION3chain 'A' and (resid 769 through 810 )A769 - 810
4X-RAY DIFFRACTION4chain 'A' and (resid 811 through 940 )A811 - 940
5X-RAY DIFFRACTION5chain 'A' and (resid 941 through 960 )A941 - 960
6X-RAY DIFFRACTION6chain 'A' and (resid 961 through 984 )A961 - 984
7X-RAY DIFFRACTION7chain 'B' and (resid 700 through 732 )B700 - 732
8X-RAY DIFFRACTION8chain 'B' and (resid 733 through 752 )B733 - 752
9X-RAY DIFFRACTION9chain 'B' and (resid 753 through 768 )B753 - 768
10X-RAY DIFFRACTION10chain 'B' and (resid 769 through 830 )B769 - 830
11X-RAY DIFFRACTION11chain 'B' and (resid 831 through 853 )B831 - 853
12X-RAY DIFFRACTION12chain 'B' and (resid 854 through 892 )B854 - 892
13X-RAY DIFFRACTION13chain 'B' and (resid 893 through 919 )B893 - 919
14X-RAY DIFFRACTION14chain 'B' and (resid 920 through 984 )B920 - 984

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