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- PDB-5cav: EGFR kinase domain with compound 41a -

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Basic information

Entry
Database: PDB / ID: 5cav
TitleEGFR kinase domain with compound 41a
ComponentsEpidermal growth factor receptor
KeywordsTransferase/transferase inhibitor / protein kinase inhibitor / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 / epidermal growth factor binding / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / hydrogen peroxide metabolic process / ERBB2-EGFR signaling pathway / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / protein tyrosine kinase activator activity / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / response to cobalamin / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / 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 / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / regulation of ERK1 and ERK2 cascade / SHC1 events in ERBB2 signaling / ossification / cellular response to dexamethasone stimulus / neurogenesis / positive regulation of synaptic transmission, glutamatergic / positive regulation of epithelial cell proliferation / neuron projection morphogenesis / basal plasma membrane / epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / Signaling by ERBB2 TMD/JMD mutants / lung development / EGFR downregulation / positive regulation of smooth muscle cell proliferation / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / kinase binding / Downregulation of ERBB2 signaling / positive regulation of miRNA transcription / peptidyl-tyrosine phosphorylation / cell-cell adhesion / ruffle membrane
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-4ZQ / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsEigenbrot, C. / Yu, C.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.
Authors: Heald, R. / Bowman, K.K. / Bryan, M.C. / Burdick, D. / Chan, B. / Chan, E. / Chen, Y. / Clausen, S. / Dominguez-Fernandez, B. / Eigenbrot, C. / Elliott, R. / Hanan, E.J. / Jackson, P. / ...Authors: Heald, R. / Bowman, K.K. / Bryan, M.C. / Burdick, D. / Chan, B. / Chan, E. / Chen, Y. / Clausen, S. / Dominguez-Fernandez, B. / Eigenbrot, C. / Elliott, R. / Hanan, E.J. / Jackson, P. / Knight, J. / La, H. / Lainchbury, M. / Malek, S. / Mann, S. / Merchant, M. / Mortara, K. / Purkey, H. / Schaefer, G. / Schmidt, S. / Seward, E. / Sideris, S. / Shao, L. / Wang, S. / Yeap, K. / Yen, I. / Yu, C. / Heffron, T.P.
History
DepositionJun 30, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 28, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2015Group: Database references
Revision 1.2Dec 2, 2015Group: Database references
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1332
Polymers37,6491
Non-polymers4831
Water362
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.310, 146.310, 146.310
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: 37649.441 Da / Num. of mol.: 1
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-4ZQ / (1R)-1-{6-({2-[(3R,4S)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl}amino)-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-imidazo[4,5-c]pyridin-2-yl}ethanol


Mass: 483.463 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H25F4N7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.47 Å3/Da / Density % sol: 64.51 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: sodium/potassium tartrate

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 18, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.7→23.5 Å / Num. obs: 13899 / % possible obs: 99.17 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5 % / Biso Wilson estimate: 68.8 Å2 / Rsym value: 0.055 / Net I/σ(I): 19.4

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.73→23.48 Å / Cor.coef. Fo:Fc: 0.9452 / Cor.coef. Fo:Fc free: 0.9243 / SU R Cruickshank DPI: 0.427 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.399 / SU Rfree Blow DPI: 0.259 / SU Rfree Cruickshank DPI: 0.267
RfactorNum. reflection% reflectionSelection details
Rfree0.2313 587 4.23 %RANDOM
Rwork0.197 ---
obs0.1984 13878 99.18 %-
Displacement parametersBiso mean: 77.73 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.468 Å
Refinement stepCycle: 1 / Resolution: 2.73→23.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2448 0 34 2 2484
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082541HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.053451HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d896SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes63HARMONIC2
X-RAY DIFFRACTIONt_gen_planes353HARMONIC5
X-RAY DIFFRACTIONt_it2541HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.34
X-RAY DIFFRACTIONt_other_torsion19.55
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion329SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2858SEMIHARMONIC4
LS refinement shellResolution: 2.73→2.95 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2554 104 3.64 %
Rwork0.2362 2753 -
all0.2369 2857 -
obs--99.18 %
Refinement TLS params.

T13: 0.152 Å2 / 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)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.02811.1106-0.29031.30820.98395.4007-0.044-0.2298-0.0327-0.2241-0.0409-0.3474-0.10250.42680.0849-0.0742-0.0827-0.08380.11120.043-54.44387.3915-29.9755
22.63720.8162-1.18294.2762-1.69781.9956-0.0496-0.3338-0.3879-0.5442-0.3686-0.54420.36550.25450.4182-0.1230.0143-0.07650.152-0.1185-60.8236-16.0366-23.7403
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|696 - A|786 A|1003 - A|1020}
2X-RAY DIFFRACTION2{A|787 - A|987 A|1101 - A|1101}

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