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- PDB-8eme: EGFR(T790M/V948R) in complex with ZNL-0056 -

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Basic information

Entry
Database: PDB / ID: 8eme
TitleEGFR(T790M/V948R) in complex with ZNL-0056
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGFR / kinase / covalent / inhibitor / TRANSFERASE / 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 / 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
Chem-ZNL / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.32 Å
AuthorsBeyett, T.S. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA116020-16 United States
CitationJournal: Acs Cent.Sci. / Year: 2024
Title: Molecular Bidents with Two Electrophilic Warheads as a New Pharmacological Modality
Authors: Li, Z. / Jiang, J. / Ficarro, S.B. / Beyett, T.S. / To, C. / Tavares, I. / Zhu, Y. / Li, J. / Eck, M.J. / Janne, P.A. / Marto, J.A. / Zhang, T. / Che, J. / Gray, N.S.
History
DepositionSep 27, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Epidermal growth factor receptor
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,9273
Polymers75,4492
Non-polymers4781
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2920 Å2
ΔGint-18 kcal/mol
Surface area26690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)34.874, 99.992, 87.023
Angle α, β, γ (deg.)90.000, 100.800, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and resid 702 through 1007)
21(chain B and (resid 702 through 747 or resid 755...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ALAALAMETMET(chain A and resid 702 through 1007)AB702 - 100711 - 316
21ALAALALEULEU(chain B and (resid 702 through 747 or resid 755...BA702 - 74711 - 56
22ALAALAARGARG(chain B and (resid 702 through 747 or resid 755...BA755 - 83264 - 141
23ARGARGPHEPHE(chain B and (resid 702 through 747 or resid 755...BA836 - 856145 - 165
24ILEILELEULEU(chain B and (resid 702 through 747 or resid 755...BA878 - 979187 - 288
25PROPROMETMET(chain B and (resid 702 through 747 or resid 755...BA990 - 1007299 - 316

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Components

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


Mass: 37724.598 Da / Num. of mol.: 2 / Fragment: Kinase domain, residues 695-1022 / 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-ZNL / N-{7-methyl-1-[(3S)-1-(prop-2-enoyl)azepan-3-yl]-1H-benzimidazol-2-yl}-5-(prop-2-enamido)thiophene-3-carboxamide


Mass: 477.579 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N5O3S / Feature type: SUBJECT OF INVESTIGATION
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: 37.73 % / Description: Plate
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.7 / Details: 0.1 M Bis-Tris pH 5.7, 25-30% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3.32→64.97 Å / Num. obs: 8682 / % possible obs: 99.3 % / Redundancy: 3.8 % / Biso Wilson estimate: 87.37 Å2 / Rpim(I) all: 0.175 / Rrim(I) all: 0.346 / Net I/σ(I): 3.6 / Num. measured all: 33246
Reflection shell

Num. measured all: 1654 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) all% possible all
3.32-3.383.90.74250.8321.66399.5
9-64.993.716.44480.0430.08699.1

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DUK

6duk


Resolution: 3.32→50 Å / SU ML: 0.54 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 35.99 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3184 497 5.76 %
Rwork0.283 8137 -
obs0.2852 8634 98.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 256.56 Å2 / Biso mean: 101.3941 Å2 / Biso min: 33.31 Å2
Refinement stepCycle: final / Resolution: 3.32→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4427 0 34 0 4461
Biso mean--73.67 --
Num. residues----549
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2478X-RAY DIFFRACTION12.654TORSIONAL
12B2478X-RAY DIFFRACTION12.654TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.32-3.650.37861180.33112032215099
3.65-4.180.35911090.31012053216299
4.18-5.270.33371450.29211986213198
5.27-500.26831250.24642066219199
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)
11.3022-1.25761.01811.0831-0.90592.97160.34690.5696-0.2343-0.6037-0.8213-0.18751.3942-0.50350.45910.6097-0.28310.1741.1240.2230.7251-8.9256-36.57418.9131
23.6061-0.4555-0.01731.71910.59253.5945-0.56820.1040.38180.06480.3569-0.2075-0.5004-0.41250.23270.6234-0.0773-0.05790.2447-0.10150.3704-0.9271-23.24529.336
34.5359-0.51960.88033.67260.75765.4929-0.5163-0.04810.0142-1.25850.1288-0.01810.09340.46220.26920.9074-0.1144-0.04780.41350.30430.4354-0.4604-27.41-5.7859
41.7155-0.01220.941.63661.50353.5731-0.61110.56590.1231-2.15480.0224-0.1721-0.71671.01960.05221.2947-0.2553-0.03940.5562-0.04420.43456.945-18.5575-8.4362
50.3083-0.12220.00980.2944-0.38510.716-0.5966-0.26370.1546-0.40290.09780.0229-0.4846-0.0605-0.01470.3557-0.7773-0.34690.4907-0.57390.66490.7016-9.191715.8364
60.2714-0.7689-0.18324.3489-0.91691.38780.5277-0.67321.0258-0.9189-0.44221.219-0.3638-0.3131-0.22760.84330.5855-0.04741.5958-0.58651.2144-9.7684-3.191926.5983
72.54390.1217-0.88241.2751.44412.58670.4075-0.29350.91110.0778-0.01080.4116-0.6137-0.42030.06980.6821-0.1082-0.02551.7967-0.68850.9252-14.0964-9.784931.3244
83.98190.7049-1.28250.766-1.17621.87480.1218-0.98021.09550.4419-0.49610.4869-0.69680.83920.12250.0930.19250.03691.2704-0.3171.1744-6.2337-1.810832.8311
92.28561.25242.69595.0043-2.56286.99310.0762-0.37610.2772-0.5205-1.23310.1885-0.7387-0.52380.56280.8746-0.0894-0.14391.5227-0.18810.252-2.8315-5.612533.731
102.84381.3144-0.47360.6798-0.4251.62240.5995-0.5540.57810.3076-0.14140.66090.0007-0.80920.37620.4006-0.3612-0.09241.631-0.56420.6276-7.6431-21.530241.5181
113.8811-0.5147-2.6214.9767-1.73444.02641.06940.11930.63240.7343-0.9358-0.5093-0.2498-0.06940.49290.6526-0.5819-0.16232.06790.32330.54477.2161-19.824944.1924
121.4745-2.0171-0.51714.4261-0.64392.09460.6926-0.10330.22961.1257-0.71510.24580.0294-0.42070.11451.0901-0.6352-0.01031.5587-0.04140.76350.4189-9.781748.6289
130.2167-0.27470.22020.76830.30321.4912-0.08390.22930.16571.267-0.3835-0.3857-0.230.2673-0.03531.726-1.2399-0.2292.1656-0.1836-0.36493.1275-16.728360.076
140.0148-0.1514-0.04793.2074-0.25891.67270.67-0.4559-0.39440.7787-0.2278-0.3771.0909-0.0901-0.24691.3565-0.9628-0.5912.10870.45030.8413.4185-25.961349.8107
152.18090.67342.45721.3351.92383.95350.9985-0.3351-0.58910.7406-0.3299-0.9351-0.3987-0.8314-0.55250.8075-0.20860.10461.17560.0320.58992.3234-28.192630.5218
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 702 through 768 )B702 - 768
2X-RAY DIFFRACTION2chain 'B' and (resid 769 through 853 )B769 - 853
3X-RAY DIFFRACTION3chain 'B' and (resid 854 through 919 )B854 - 919
4X-RAY DIFFRACTION4chain 'B' and (resid 920 through 978 )B920 - 978
5X-RAY DIFFRACTION5chain 'B' and (resid 979 through 1007 )B979 - 1007
6X-RAY DIFFRACTION6chain 'A' and (resid 700 through 716 )A700 - 716
7X-RAY DIFFRACTION7chain 'A' and (resid 717 through 736 )A717 - 736
8X-RAY DIFFRACTION8chain 'A' and (resid 737 through 768 )A737 - 768
9X-RAY DIFFRACTION9chain 'A' and (resid 769 through 786 )A769 - 786
10X-RAY DIFFRACTION10chain 'A' and (resid 787 through 810 )A787 - 810
11X-RAY DIFFRACTION11chain 'A' and (resid 811 through 830 )A811 - 830
12X-RAY DIFFRACTION12chain 'A' and (resid 831 through 892 )A831 - 892
13X-RAY DIFFRACTION13chain 'A' and (resid 893 through 960 )A893 - 960
14X-RAY DIFFRACTION14chain 'A' and (resid 961 through 978 )A961 - 978
15X-RAY DIFFRACTION15chain 'A' and (resid 979 through 1007 )A979 - 1007

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