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- PDB-7a6j: Crystal Structure of EGFR-T790M/V948R in Complex with Poziotinib -

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Basic information

Entry
Database: PDB / ID: 7a6j
TitleCrystal Structure of EGFR-T790M/V948R in Complex with Poziotinib
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M/V948R / Exon20 / covalent
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / tongue development / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / response to cobalamin / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / hepatocyte growth factor receptor activity / platelet-derived growth factor beta-receptor activity / placental growth factor receptor activity / brain-derived neurotrophic factor receptor activity / boss receptor activity / platelet-derived growth factor alpha-receptor activity / epidermal growth factor receptor activity / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / macrophage colony-stimulating factor receptor activity / positive regulation of bone resorption / protein tyrosine kinase collagen receptor activity / stem cell factor receptor activity / Signaling by ERBB4 / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / insulin-like growth factor receptor activity / transmembrane-ephrin receptor activity / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / GPI-linked ephrin receptor activity / vascular endothelial growth factor receptor activity / peptidyl-tyrosine autophosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / embryonic placenta development / fibroblast growth factor receptor activity / insulin receptor activity / salivary gland morphogenesis / positive regulation of vasoconstriction / Signaling by ERBB2 / positive regulation of glial cell proliferation / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / cellular response to dexamethasone stimulus / GRB2 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / neuron projection morphogenesis / Signal transduction by L1 / positive regulation of smooth muscle cell proliferation / positive regulation of protein localization to plasma membrane / liver regeneration / astrocyte activation / cellular response to amino acid stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to estradiol stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / lung development / EGFR downregulation / synaptic membrane / peptidyl-tyrosine phosphorylation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII
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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-R2E / 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, European Union, 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-800400European Union
CitationJournal: J.Med.Chem. / Year: 2022
Title: Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors.
Authors: Lategahn, J. / Tumbrink, H.L. / Schultz-Fademrecht, C. / Heimsoeth, A. / Werr, L. / Niggenaber, J. / Keul, M. / Parmaksiz, F. / Baumann, M. / Menninger, S. / Zent, E. / Landel, I. / Weisner, ...Authors: Lategahn, J. / Tumbrink, H.L. / Schultz-Fademrecht, C. / Heimsoeth, A. / Werr, L. / Niggenaber, J. / Keul, M. / Parmaksiz, F. / Baumann, M. / Menninger, S. / Zent, E. / Landel, I. / Weisner, J. / Jeyakumar, K. / Heyden, L. / Russ, N. / Muller, F. / Lorenz, C. / Bragelmann, J. / Spille, I. / Grabe, T. / Muller, M.P. / Heuckmann, J.M. / Klebl, B.M. / Nussbaumer, P. / Sos, M.L. / Rauh, D.
History
DepositionAug 25, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 25, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 5, 2022Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 1.4Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.5Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)77,54712
Polymers75,9282
Non-polymers1,61910
Water2,558142
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8367
Polymers37,9641
Non-polymers8726
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7115
Polymers37,9641
Non-polymers7484
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.330, 81.760, 89.850
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 699 through 708 or (resid 709...
21(chain B and (resid 699 through 715 or (resid 716...

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
11PROPROLYSLYS(chain A and (resid 699 through 708 or (resid 709...AA699 - 70810 - 19
12GLUGLUGLUGLU(chain A and (resid 699 through 708 or (resid 709...AA70920
13PROPROGLNGLN(chain A and (resid 699 through 708 or (resid 709...AA699 - 98210 - 293
14PROPROGLNGLN(chain A and (resid 699 through 708 or (resid 709...AA699 - 98210 - 293
15PROPROGLNGLN(chain A and (resid 699 through 708 or (resid 709...AA699 - 98210 - 293
16PROPROGLNGLN(chain A and (resid 699 through 708 or (resid 709...AA699 - 98210 - 293
21PROPROILEILE(chain B and (resid 699 through 715 or (resid 716...BB699 - 71510 - 26
22LYSLYSLYSLYS(chain B and (resid 699 through 715 or (resid 716...BB71627

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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-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


Mass: 493.358 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23Cl2FN4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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
Details: 20.0 % PEG3350, 100 mM MgSO4, 4 % ethylen glycole, 7.5 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: 0.915 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 24, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.915 Å / Relative weight: 1
ReflectionResolution: 2→44.92 Å / Num. obs: 38568 / % possible obs: 99.8 % / Redundancy: 13.06 % / CC1/2: 0.999 / Rrim(I) all: 0.089 / Net I/σ(I): 18.78
Reflection shellResolution: 2→2.1 Å / Redundancy: 12.49 % / Mean I/σ(I) obs: 1.8 / Num. unique obs: 5173 / CC1/2: 0.838 / Rrim(I) all: 1.441 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6S8A

6s8a


Resolution: 2→44.92 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2159 1928 5 %
Rwork0.1902 36640 -
obs0.1915 38568 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 111.17 Å2 / Biso mean: 48.7592 Å2 / Biso min: 26.9 Å2
Refinement stepCycle: final / Resolution: 2→44.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4175 0 126 142 4443
Biso mean--50.07 46.8 -
Num. residues----541
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2448X-RAY DIFFRACTION10.439TORSIONAL
12B2448X-RAY DIFFRACTION10.439TORSIONAL
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.050.33231350.285725672702100
2.05-2.110.28391350.260425842719100
2.11-2.170.3221360.239725732709100
2.17-2.240.28251350.24882573270899
2.24-2.320.32171340.27872554268899
2.32-2.410.27051370.214525952732100
2.41-2.520.30621370.216925972734100
2.52-2.650.25861370.214526112748100
2.65-2.820.2351380.211926162754100
2.82-3.040.2621380.212826192757100
3.04-3.340.22611370.196326192756100
3.34-3.820.17821400.17126502790100
3.83-4.820.15051410.143626812822100
4.82-44.920.1941480.174228012949100
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)
11.6719-0.18460.03540.4457-0.01934.221-0.0359-0.1081-0.05140.09-0.00750.11640.18890.0540.02760.2629-0.0040.00620.2521-0.01170.3475-41.29625.0176-2.9692
24.7190.5420.36073.15230.41773.0043-0.08250.25150.1978-0.1931-0.11630.15810.0619-0.21850.19680.26730.0228-0.03760.3039-0.01050.2594-53.73427.2541-21.7783
32.29280.54730.70283.38650.74721.9403-0.1720.10060.3512-0.1710.0860.2529-0.28450.26660.11410.2401-0.0439-0.01020.30740.00240.2601-21.956312.8974-8.3069
44.1409-0.1264-0.62251.572-0.14473.3356-0.11290.2024-0.3035-0.12420.0133-0.26460.39450.86290.10710.34390.10580.00240.4706-0.03330.3096-11.3075-6.0243-10.3225
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 699 through 853 )A699 - 853
2X-RAY DIFFRACTION2chain 'A' and (resid 854 through 982 )A854 - 982
3X-RAY DIFFRACTION3chain 'B' and (resid 699 through 830 )B699 - 830
4X-RAY DIFFRACTION4chain 'B' and (resid 831 through 984 )B831 - 984

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