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- PDB-8d76: Crystal Structure of EGFR LRTM with compound 24 -

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Basic information

Entry
Database: PDB / ID: 8d76
TitleCrystal Structure of EGFR LRTM with compound 24
ComponentsEpidermal growth factor receptor
KeywordsSIGNALING PROTEIN / Protein Kinase / inhibitor / kinase domain / mutation
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / 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 / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / 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 / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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 / 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-QFO / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsKim, J.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.
Authors: Eno, M.S. / Brubaker, J.D. / Campbell, J.E. / De Savi, C. / Guzi, T.J. / Williams, B.D. / Wilson, D. / Wilson, K. / Brooijmans, N. / Kim, J. / Ozen, A. / Perola, E. / Hsieh, J. / Brown, V. / ...Authors: Eno, M.S. / Brubaker, J.D. / Campbell, J.E. / De Savi, C. / Guzi, T.J. / Williams, B.D. / Wilson, D. / Wilson, K. / Brooijmans, N. / Kim, J. / Ozen, A. / Perola, E. / Hsieh, J. / Brown, V. / Fetalvero, K. / Garner, A. / Zhang, Z. / Stevison, F. / Woessner, R. / Singh, J. / Timsit, Y. / Kinkema, C. / Medendorp, C. / Lee, C. / Albayya, F. / Zalutskaya, A. / Schalm, S. / Dineen, T.A.
History
DepositionJun 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 18, 2023Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)81,23510
Polymers79,5962
Non-polymers1,6408
Water10,971609
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7106
Polymers39,7981
Non-polymers9125
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5264
Polymers39,7981
Non-polymers7283
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.535, 50.316, 85.875
Angle α, β, γ (deg.)104.190, 101.730, 90.120
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: LEU / Beg label comp-ID: LEU / End auth comp-ID: ALA / End label comp-ID: ALA / Refine code: _ / Auth seq-ID: 703 - 1013 / Label seq-ID: 29 - 339

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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


Mass: 39797.777 Da / Num. of mol.: 2
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-QFO / (3S,4R)-3-fluoro-1-(4-{[8-{3-[(methanesulfonyl)methyl]azetidin-1-yl}-5-(propan-2-yl)-2,7-naphthyridin-3-yl]amino}pyrimidin-2-yl)-3-methylpiperidin-4-ol


Mass: 543.657 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H34FN7O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 609 / 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: 2.14 Å3/Da / Density % sol: 42.45 %
Crystal growTemperature: 285 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1 M sodium acetate pH 5.3, 0.2 M potassium acetate, 3% PEG 8000.

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Data collection

DiffractionMean temperature: 110 K / Ambient temp details: 2018-07-18 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 2.39→48.7 Å / Num. obs: 25531 / % possible obs: 98 % / Redundancy: 3.5 % / Rrim(I) all: 0.08 / Net I/σ(I): 10.8
Reflection shellResolution: 2.39→2.43 Å / Redundancy: 3.5 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1289 / Rrim(I) all: 0.63 / % possible all: 96.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4i22

4i22


Resolution: 2.4→30 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.913 / SU B: 11.121 / SU ML: 0.247 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.161 / ESU R Free: 0.315 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.26 1260 5 %RANDOM
Rwork0.156 ---
obs0.1613 23969 97.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 157.35 Å2 / Biso mean: 61.506 Å2 / Biso min: 33.84 Å2
Baniso -1Baniso -2Baniso -3
1--1.38 Å2-0.35 Å2-0.2 Å2
2--0.77 Å2-0.46 Å2
3---0.77 Å2
Refinement stepCycle: final / Resolution: 2.4→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5025 0 112 609 5746
Biso mean--62.84 67.21 -
Num. residues----625
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0135288
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175076
X-RAY DIFFRACTIONr_angle_refined_deg1.361.6447163
X-RAY DIFFRACTIONr_angle_other_deg1.1691.57911788
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3895637
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.93421.908262
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.52115972
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1931536
X-RAY DIFFRACTIONr_chiral_restr0.0630.2674
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.025742
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021070
Refine LS restraints NCS

Ens-ID: 1 / Number: 10398 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.05 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.4→2.462 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.32 104 -
Rwork0.244 1723 -
all-1827 -
obs--96.92 %

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