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- PDB-8f1w: EGFR(T790M/V948R) kinase in complex with poziotinib -

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Basic information

Entry
Database: PDB / ID: 8f1w
TitleEGFR(T790M/V948R) kinase in complex with poziotinib
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGFR / kinase / 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 / 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
Chem-R2E / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 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: To be published
Title: EGFR(T790M/V948R) kinase in complex with poziotinib
Authors: Beyett, T.S. / Eck, M.J.
History
DepositionNov 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release

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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
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,8728
Polymers150,8984
Non-polymers1,9734
Water0
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2182
Polymers37,7251
Non-polymers4931
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2182
Polymers37,7251
Non-polymers4931
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2182
Polymers37,7251
Non-polymers4931
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2182
Polymers37,7251
Non-polymers4931
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)70.790, 102.534, 87.328
Angle α, β, γ (deg.)90.00, 102.31, 90.00
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: 37724.598 Da / Num. of mol.: 4 / Fragment: kinase domain / Mutation: T790M, V948R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-R2E / 1-[4-[4-[[3,4-bis(chloranyl)-2-fluoranyl-phenyl]amino]-7-methoxy-quinazolin-6-yl]oxypiperidin-1-yl]propan-1-one / Poziotinib, bound form / Poziotinib


Mass: 493.358 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H23Cl2FN4O3 / 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

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-C / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 23, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 3.2→102.53 Å / Num. obs: 19840 / % possible obs: 97.9 % / Redundancy: 3 % / CC1/2: 0.959 / Rmerge(I) obs: 0.215 / Rpim(I) all: 0.145 / Rrim(I) all: 0.261 / Net I/σ(I): 3.3 / Num. measured all: 60222
Reflection shellResolution: 3.2→3.25 Å / % possible obs: 96.8 % / Redundancy: 3.1 % / Rmerge(I) obs: 0.573 / Num. measured all: 2968 / Num. unique obs: 969 / CC1/2: 0.855 / Rpim(I) all: 0.386 / Rrim(I) all: 0.693 / Net I/σ(I) obs: 0.8

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.20.1refinement
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DUK

6duk


Resolution: 3.2→85.32 Å / SU ML: 0.54 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 29.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2741 1025 5.21 %
Rwork0.2309 --
obs0.2332 19690 97.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.2→85.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9526 0 132 0 9658
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0039899
X-RAY DIFFRACTIONf_angle_d0.56213389
X-RAY DIFFRACTIONf_dihedral_angle_d14.6613776
X-RAY DIFFRACTIONf_chiral_restr0.0441475
X-RAY DIFFRACTIONf_plane_restr0.0041670
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.2-3.370.37481430.30552643X-RAY DIFFRACTION97
3.37-3.580.33781320.28522669X-RAY DIFFRACTION98
3.58-3.850.2891290.24792649X-RAY DIFFRACTION96
3.85-4.240.25181690.22522672X-RAY DIFFRACTION99
4.24-4.860.281510.20322679X-RAY DIFFRACTION98
4.86-6.120.24471610.21832649X-RAY DIFFRACTION97
6.12-85.320.22651400.19512704X-RAY DIFFRACTION96
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)
11.00041.05690.77482.29621.46812.0209-0.04690.1293-0.5626-0.61130.3839-0.48420.46950.47380.75580.6050.227-0.01140.304-0.63790.491438.26137.5823-17.2215
22.1689-0.26930.18793.26440.42831.30570.1520.0788-0.31130.0645-0.10080.0640.2780.0787-0.05930.3119-0.0438-0.08320.42040.03820.266531.967614.5241-5.1541
33.08160.6057-0.05343.03840.80192.3433-0.22430.0264-0.8127-0.50610.2307-0.29820.27520.3992-0.01450.37030.0436-0.03460.46280.06190.345529.78169.790610.8005
41.57070.26360.1542.21470.09912.61470.0898-0.5830.2044-0.237-0.2108-0.40370.2379-0.28160.08530.30820.0756-0.16780.53610.00310.237723.940922.072916.2449
51.7986-0.5999-1.06910.4681-0.58396.6996-0.27220.58971.1174-0.33050.11090.0556-0.2569-0.18360.30310.2931-0.0023-0.05790.5723-0.10720.590126.910335.3223-5.2998
62.4404-1.115-0.8392.3333-0.8912.1517-0.4979-0.46610.43450.3656-0.1844-0.1626-0.7822-0.05110.30680.4286-0.0455-0.08420.376-0.17460.394539.167738.8824-21.9932
71.85130.92741.55383.37781.50863.24060.0048-0.0428-0.00840.14630.28640.01510.2310.259-0.3150.3603-0.03040.0290.46280.06220.266128.455730.7529-32.5167
82.12310.0264-0.48692.4063-0.08112.4712-0.16520.25310.1998-0.3860.09730.1493-0.36920.00670.10930.40260.0014-0.01430.37670.01310.234624.424729.1877-49.4347
90.1178-0.44390.43952.4429-0.13.91260.19520.6901-0.15021.1033-0.0137-0.44080.3316-0.5145-0.04020.6956-0.2452-0.27220.68010.02490.666526.232713.4597-28.4518
108.0789-1.135-4.43242.24970.77923.10670.9591.0330.4867-0.383-0.1364-0.021-0.2680.035-0.56830.69180.0457-0.06770.5744-0.16580.42273.045740.8585-23.0176
112.7478-1.34651.28791.7814-0.88143.1761-0.45860.3193-0.02910.1927-0.26150.060.198-0.3205-1.18510.19160.2930.44480.4069-0.260.501372.67142.8287-19.7545
123.12650.54922.66266.21791.91353.8911-0.0886-0.02470.6896-0.22930.01040.1437-0.5606-0.4156-0.00810.4278-0.06420.06560.5788-0.07370.324862.365442.9401-27.1435
133.30311.02050.71542.60591.03843.02930.42220.4132-0.3040.4320.1194-0.22210.24150.3551-0.44080.37780.0061-0.08160.3744-0.02550.248464.359827.0742-35.1675
143.7418-0.2101-0.47524.2146-1.64312.1620.1157-0.35240.2285-0.4730.1088-0.05770.4694-0.191-0.11190.4898-0.02370.04150.40.00850.368264.42234.4844-49.5397
154.35340.1485-1.97891.38150.67633.9429-0.25020.9391-0.5319-0.4595-0.0253-0.0392-0.0749-0.39170.04130.37520.04080.00530.2825-0.05260.470457.448324.9356-54.3383
165.2563-0.7658-1.15594.36390.19484.001-0.51870.4384-0.49250.1206-0.29570.37460.3717-0.1660.20950.78380.0298-0.06050.4896-0.13290.372352.189517.3508-42.5003
171.47790.35891.10010.8437-1.16193.47190.2741-0.112-0.53070.1428-0.28670.34480.94160.1966-0.10720.85420.0266-0.05350.4421-0.02120.623263.565113.0343-30.0965
183.691-0.25871.68692.2155-0.68136.05920.46160.8138-0.31540.1047-0.3171-0.42321.24130.8517-0.13160.4890.0674-0.14630.4485-0.0480.544175.666113.5535-14.1604
191.81520.90420.12367.6457-2.29580.77440.2666-0.4763-1.2518-1.08140.29860.23480.5919-0.2959-0.32050.5307-0.0631-0.0430.9384-0.23740.663468.19561.7601-4.3416
202.5784-0.7878-0.02992.46861.63072.61740.1624-0.460.2616-0.2810.3766-0.39650.5484-0.2054-0.38380.52840.02040.04920.45680.17120.415269.103221.5201-4.7556
211.8770.70590.23944.44360.10342.1333-0.107-0.1539-0.147-0.35270.3612-0.58230.19960.1843-0.17760.2161-0.01450.10030.3196-0.06050.291959.413222.63210.2618
220.23860.23050.19810.4617-0.13530.66450.2582-0.22420.5472-0.53230.2885-0.6972-0.14210.0658-0.42510.7250.07160.1820.528-0.0710.42170.73778.56497.829
231.4104-0.6169-0.16091.5017-0.53812.2321-0.0930.0481-0.12140.00520.0262-0.12690.0269-0.01690.00880.30120.0090.00380.4082-0.10570.31758.659322.729614.8769
241.0724-0.0108-1.52120.6797-1.25834.47160.0042-0.4813-0.0798-0.20020.0684-0.3464-0.0852-0.22410.20670.4098-0.1076-0.13230.5962-0.050.554560.864937.9997-6.2215
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 701 through 717 )
2X-RAY DIFFRACTION2chain 'A' and (resid 718 through 853 )
3X-RAY DIFFRACTION3chain 'A' and (resid 854 through 908 )
4X-RAY DIFFRACTION4chain 'A' and (resid 909 through 978 )
5X-RAY DIFFRACTION5chain 'A' and (resid 979 through 1007 )
6X-RAY DIFFRACTION6chain 'B' and (resid 700 through 756 )
7X-RAY DIFFRACTION7chain 'B' and (resid 757 through 853 )
8X-RAY DIFFRACTION8chain 'B' and (resid 854 through 978 )
9X-RAY DIFFRACTION9chain 'B' and (resid 979 through 1007 )
10X-RAY DIFFRACTION10chain 'C' and (resid 700 through 731 )
11X-RAY DIFFRACTION11chain 'C' and (resid 732 through 756 )
12X-RAY DIFFRACTION12chain 'C' and (resid 757 through 785 )
13X-RAY DIFFRACTION13chain 'C' and (resid 786 through 853 )
14X-RAY DIFFRACTION14chain 'C' and (resid 854 through 928 )
15X-RAY DIFFRACTION15chain 'C' and (resid 929 through 960 )
16X-RAY DIFFRACTION16chain 'C' and (resid 961 through 977 )
17X-RAY DIFFRACTION17chain 'C' and (resid 978 through 1007 )
18X-RAY DIFFRACTION18chain 'D' and (resid 700 through 747 )
19X-RAY DIFFRACTION19chain 'D' and (resid 748 through 768 )
20X-RAY DIFFRACTION20chain 'D' and (resid 769 through 810 )
21X-RAY DIFFRACTION21chain 'D' and (resid 811 through 853 )
22X-RAY DIFFRACTION22chain 'D' and (resid 854 through 877 )
23X-RAY DIFFRACTION23chain 'D' and (resid 878 through 978 )
24X-RAY DIFFRACTION24chain 'D' and (resid 979 through 1007 )

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