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- PDB-6tg0: Crystal Structure of EGFR T790M/V948R in Complex with Covalent Py... -

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Basic information

Entry
Database: PDB / ID: 6tg0
TitleCrystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 21a
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / HER2 / EGFR / covalent Inhibitors
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-N78 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 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: J.Med.Chem. / Year: 2020
Title: Targeting Her2-insYVMA with Covalent Inhibitors-A Focused Compound Screening and Structure-Based Design Approach.
Authors: Lategahn, J. / Hardick, J. / Grabe, T. / Niggenaber, J. / Jeyakumar, K. / Keul, M. / Tumbrink, H.L. / Becker, C. / Hodson, L. / Kirschner, T. / Klovekorn, P. / Ketzer, J. / Baumann, M. / ...Authors: Lategahn, J. / Hardick, J. / Grabe, T. / Niggenaber, J. / Jeyakumar, K. / Keul, M. / Tumbrink, H.L. / Becker, C. / Hodson, L. / Kirschner, T. / Klovekorn, P. / Ketzer, J. / Baumann, M. / Terheyden, S. / Unger, A. / Weisner, J. / Muller, M.P. / van Otterlo, W.A.L. / Bauer, S. / Rauh, D.
History
DepositionNov 14, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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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)77,71412
Polymers75,9282
Non-polymers1,78610
Water6,269348
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8576
Polymers37,9641
Non-polymers8935
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8576
Polymers37,9641
Non-polymers8935
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.800, 82.000, 90.200
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 700 through 708 or (resid 709...
21(chain B and ((resid 700 through 702 and (name N...

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
11ASNASNLYSLYS(chain A and (resid 700 through 708 or (resid 709...AA700 - 70811 - 19
12GLUGLUGLUGLU(chain A and (resid 700 through 708 or (resid 709...AA70920
13ASNASNGLUGLU(chain A and (resid 700 through 708 or (resid 709...AA700 - 98511 - 296
14ASNASNGLUGLU(chain A and (resid 700 through 708 or (resid 709...AA700 - 98511 - 296
15ASNASNGLUGLU(chain A and (resid 700 through 708 or (resid 709...AA700 - 98511 - 296
16ASNASNGLUGLU(chain A and (resid 700 through 708 or (resid 709...AA700 - 98511 - 296
21ASNASNALAALA(chain B and ((resid 700 through 702 and (name N...BB700 - 70211 - 13
22ALAALAASPASP(chain B and ((resid 700 through 702 and (name N...BB698 - 9849 - 295
23ALAALAASPASP(chain B and ((resid 700 through 702 and (name N...BB698 - 9849 - 295
24ALAALAASPASP(chain B and ((resid 700 through 702 and (name N...BB698 - 9849 - 295

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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-N78 / ~{N}-[5-[4-[[4-[[1,3-bis(oxidanylidene)isoindol-2-yl]methyl]phenyl]amino]-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]-2-(2-hydroxyethyloxy)phenyl]propanamide


Mass: 576.602 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H28N6O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 348 / 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: 2.28 Å3/Da / Density % sol: 46.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 27.5 % PEG3350, 100 mM MgSO4, 3 % ethylen glycole 7.0 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 PILATUS 6M / Detector: PIXEL / Date: Nov 24, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.5→47.61 Å / Num. obs: 91649 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.999 / Rrim(I) all: 0.073 / Net I/σ(I): 14.66
Reflection shellResolution: 1.5→1.6 Å / Redundancy: 6.44 % / Mean I/σ(I) obs: 2 / Num. unique obs: 15946 / CC1/2: 0.757 / Rrim(I) all: 0.841 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5j9z

5j9z


Resolution: 1.5→47.61 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 18.2
RfactorNum. reflection% reflection
Rfree0.1875 4583 5 %
Rwork0.1737 --
obs0.1744 91647 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 68.72 Å2 / Biso mean: 24.5292 Å2 / Biso min: 10.67 Å2
Refinement stepCycle: final / Resolution: 1.5→47.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4291 0 146 349 4786
Biso mean--23.08 33.24 -
Num. residues----543
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2419X-RAY DIFFRACTION9.562TORSIONAL
12B2419X-RAY DIFFRACTION9.562TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.5-1.5170.27421510.2372861
1.517-1.53490.27361510.23812866
1.5349-1.55360.23511490.2342846
1.5536-1.57330.24741510.2242863
1.5733-1.5940.25841510.21592867
1.594-1.61580.2781510.21142877
1.6158-1.63890.22971530.20742895
1.6389-1.66340.20381500.19442853
1.6634-1.68940.22921510.19432871
1.6894-1.71710.24071530.19082910
1.7171-1.74670.2361510.17872871
1.7467-1.77840.18381520.17862886
1.7784-1.81260.21091500.18032849
1.8126-1.84960.20721530.17582910
1.8496-1.88990.22131510.17352860
1.8899-1.93380.17781520.16642889
1.9338-1.98220.18061530.16622901
1.9822-2.03580.19881510.16822879
2.0358-2.09570.19511520.16632896
2.0957-2.16330.20411530.16122904
2.1633-2.24060.15621530.16112891
2.2406-2.33040.20841530.17252918
2.3304-2.43640.17551530.16912915
2.4364-2.56490.18681530.1732906
2.5649-2.72550.20051550.16662930
2.7255-2.9360.18471540.17732923
2.936-3.23130.18111550.17462948
3.2313-3.69880.16991560.17022968
3.6988-4.65940.14151570.15042982
4.6594-47.610.18741650.18073129
Refinement TLS params.Method: refined / Origin x: -31.5346 Å / Origin y: 5.3174 Å / Origin z: -10.424 Å
111213212223313233
T0.1248 Å2-0.0078 Å20.0073 Å2-0.0894 Å2-0.0041 Å2--0.1015 Å2
L0.8901 °2-0.0905 °20.1251 °2-0.2518 °2-0.0109 °2--0.6564 °2
S-0.0176 Å °-0.0288 Å °-0 Å °0.0032 Å °-0.0034 Å °-0.0096 Å °0.0138 Å °0.0947 Å °0.0186 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA700 - 985
2X-RAY DIFFRACTION1allD1001
3X-RAY DIFFRACTION1allC1201 - 4
4X-RAY DIFFRACTION1allB698 - 984
5X-RAY DIFFRACTION1allD1002
6X-RAY DIFFRACTION1allB1101
7X-RAY DIFFRACTION1allE1 - 568

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