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- PDB-8g63: Ralimetinib (LY2228820) in complex with wild type EGFR -

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Basic information

Entry
Database: PDB / ID: 8g63
TitleRalimetinib (LY2228820) in complex with wild type EGFR
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/INHIBITOR / Kinase inhibitor / TRANSFERASE / TRANSFERASE-INHIBITOR complex
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 / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / morphogenesis of an epithelial fold / 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 / positive regulation of cyclin-dependent protein serine/threonine kinase activity / Signaling by ERBB4 / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / regulation of peptidyl-tyrosine phosphorylation / 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 / embryonic placenta development / positive regulation of bone resorption / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / 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 / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / positive regulation of peptidyl-serine phosphorylation / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / basal plasma membrane / liver regeneration / epithelial cell proliferation / Signal transduction by L1 / neurogenesis / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / 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 / cell surface receptor protein tyrosine kinase signaling pathway / 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
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
ralimetinib / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsChitnis, S.P. / Heppner, D.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Advancing Translational Sciences (NIH/NCATS)UL1TR001412-07 United States
CitationJournal: Cell Chem Biol / Year: 2023
Title: Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor.
Authors: Bhattacharjee, D. / Bakar, J. / Chitnis, S.P. / Sausville, E.L. / Ashtekar, K.D. / Mendelson, B.E. / Long, K. / Smith, J.C. / Heppner, D.E. / Sheltzer, J.M.
History
DepositionFeb 14, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 3, 2024Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.2Apr 24, 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7252
Polymers37,3041
Non-polymers4211
Water52229
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)143.850, 143.850, 143.850
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23

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Components

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


Mass: 37304.129 Da / Num. of mol.: 1 / Fragment: kinase domain
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-YXT / ralimetinib / (5P)-5-[2-tert-butyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-amine


Mass: 420.526 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H29FN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 3.32 Å3/Da / Density % sol: 63 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 1.4 M Sodium Citrate, 0.1 M MES

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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: Dec 14, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.5→45.49 Å / Num. obs: 32234 / % possible obs: 99.2 % / Redundancy: 5.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.086 / Rrim(I) all: 0.095 / Net I/σ(I): 12.59
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.5-2.651.29927290.4661.4461
2.65-2.830.80725720.6770.8951
2.83-3.060.41324310.8890.4591
3.06-3.350.20922170.9720.2331
3.35-3.740.10720020.9910.121
3.74-4.320.06417870.9970.0711
4.32-5.280.04815210.9970.0531
5.28-7.410.04611650.9980.0511
7.41-45.490.0257110.9990.0281

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Processing

Software
NameVersionClassification
PHENIX1.19_4092refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→45.49 Å / SU ML: 0.37 / Cross valid method: NONE / σ(F): 1.34 / Phase error: 33.14 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2566 1595 4.95 %
Rwork0.2078 --
obs0.2102 32234 96.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.5→45.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2229 0 31 29 2289
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092311
X-RAY DIFFRACTIONf_angle_d1.0483133
X-RAY DIFFRACTIONf_dihedral_angle_d8.208305
X-RAY DIFFRACTIONf_chiral_restr0.057353
X-RAY DIFFRACTIONf_plane_restr0.008386
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.580.36341390.34272700X-RAY DIFFRACTION94
2.58-2.670.34761480.31162897X-RAY DIFFRACTION100
2.67-2.780.35881460.28832815X-RAY DIFFRACTION99
2.78-2.910.33541450.27892853X-RAY DIFFRACTION99
2.91-3.060.3291480.28172821X-RAY DIFFRACTION98
3.06-3.250.31961450.25652769X-RAY DIFFRACTION97
3.25-3.50.26661450.22262784X-RAY DIFFRACTION97
3.51-3.850.25431410.19812721X-RAY DIFFRACTION95
3.86-4.410.22751480.18032811X-RAY DIFFRACTION98
4.41-5.560.20281420.16662772X-RAY DIFFRACTION96
5.57-45.490.24021480.18122696X-RAY DIFFRACTION94

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