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- PDB-2jiv: Crystal structure of EGFR kinase domain T790M mutation in compex ... -

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Basic information

Entry
Database: PDB / ID: 2jiv
TitleCrystal structure of EGFR kinase domain T790M mutation in compex with HKI-272
ComponentsEPIDERMAL GROWTH FACTOR RECEPTOR
KeywordsTRANSFERASE / HKI272 / HKI-272 / RECEPTOR / CELL CYCLE / ATP-BINDING / TYROSINE-PROTEIN KINASE / TRANSMEMBRANE / PHOSPHORYLATION / DISEASE MUTATION / NUCLEOTIDE-BINDING / ANTI-ONCOGENE / EPIDERMAL GROWTH FACTOR
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 / positive regulation of DNA replication / 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 / 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 / kinase binding
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 / 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-HKI / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsYun, C.-H. / Mengwasser, K.E. / Toms, A.V. / Li, Y. / Woo, M.S. / Greulich, H. / Wong, K.-K. / Meyerson, M. / Eck, M.J.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2008
Title: The T790M Mutation in Egfr Kinase Causes Drug Resistance by Increasing the Affinity for ATP.
Authors: Yun, C.-H. / Mengwasser, K.E. / Toms, A.V. / Woo, M.S. / Greulich, H. / Wong, K.-K. / Meyerson, M. / Eck, M.J.
History
DepositionJul 2, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 22, 2008Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2014Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Other / Source and taxonomy / Structure summary / Version format compliance
Revision 1.2Nov 11, 2015Group: Derived calculations
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: AUTHOR PROVIDED.

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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)76,0326
Polymers74,8432
Non-polymers1,1894
Water1,11762
1
A: EPIDERMAL GROWTH FACTOR RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9802
Polymers37,4211
Non-polymers5591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: EPIDERMAL GROWTH FACTOR RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0514
Polymers37,4211
Non-polymers6303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)56.087, 98.989, 73.326
Angle α, β, γ (deg.)90.00, 109.94, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-0.69128, -0.71512, 0.10362), (-0.71339, 0.65263, -0.25524), (0.1149, -0.25036, -0.96131)
Vector: -2.66549, 0.8362, 12.5974)

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Components

#1: Protein EPIDERMAL GROWTH FACTOR RECEPTOR / / RECEPTOR TYROSINE-PROTEIN KINASE ERBB-1


Mass: 37421.301 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 695-1022 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: EGFR 696-1022 T790M / Source: (gene. exp.) HOMO SAPIENS (human) / Description: EGFR 696-1022 T790M / Plasmid: PACG2T / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P00533, EC: 2.7.1.112, receptor protein-tyrosine kinase
#2: Chemical ChemComp-HKI / N-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)butanamide / Neratinib (HKI-272), bound form


Mass: 559.059 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H31ClN6O3
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 62 / Source method: isolated from a natural source / Formula: H2O
Compound detailsRECEPTOR FOR EGF, BUT ALSO FOR OTHER MEMBERS OF THE EGF FAMILY ENGINEERED RESIDUE IN CHAIN A, THR ...RECEPTOR FOR EGF, BUT ALSO FOR OTHER MEMBERS OF THE EGF FAMILY ENGINEERED RESIDUE IN CHAIN A, THR 790 TO MET ENGINEERED RESIDUE IN CHAIN B, THR 790 TO MET
Nonpolymer detailsCYSTEINE MODIFIED BY HKI-272 (HKI): CYSTEINE RESIDUE COVALENTLY CONNECTS TO HKI-272, A IRREVERSIBLE ...CYSTEINE MODIFIED BY HKI-272 (HKI): CYSTEINE RESIDUE COVALENTLY CONNECTS TO HKI-272, A IRREVERSIBLE INHIBITOR OF THE KINASE.
Sequence detailsT790M MUTATION. CYS797 MODIFIED BY HKI-272

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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: 2.58 Å3/Da / Density % sol: 52.3 % / Description: NONE
Crystal growpH: 7.5
Details: 0.1M HEPES PH7.0, 0.2M LI2SO4, 28% PEG3350, 5MM TCEP, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97918
DetectorType: ADSC CCD / Detector: CCD / Date: Oct 28, 2006 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3.5→50 Å / Num. obs: 8699 / % possible obs: 91.3 % / Observed criterion σ(I): -3 / Redundancy: 2.7 % / Rmerge(I) obs: 0.18 / Net I/σ(I): 5.8
Reflection shellResolution: 3.5→3.77 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 2.8 / % possible all: 93

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Processing

Software
NameVersionClassification
REFMAC5.3.0026refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2GS7

2gs7


Resolution: 3.5→25 Å / Cor.coef. Fo:Fc: 0.854 / Cor.coef. Fo:Fc free: 0.806 / Cross valid method: THROUGHOUT / ESU R Free: 0.772 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. STEREO-CHEMISTRY RESTRAINTS ENFORCED DUE TO LOW RESOLUTION OF THE DIFFRACTION DATA.
RfactorNum. reflection% reflectionSelection details
Rfree0.284 428 5 %RANDOM
Rwork0.251 ---
obs0.253 8213 90.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 45.59 Å2
Baniso -1Baniso -2Baniso -3
1-5.96 Å20 Å21.93 Å2
2---1.03 Å20 Å2
3----3.62 Å2
Refinement stepCycle: LAST / Resolution: 3.5→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4277 0 82 62 4421
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0224463
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0461.9946044
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg1.6845538
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.84223.647170
X-RAY DIFFRACTIONr_dihedral_angle_3_deg29.22615798
X-RAY DIFFRACTIONr_dihedral_angle_4_deg25.581525
X-RAY DIFFRACTIONr_chiral_restr0.3990.2681
X-RAY DIFFRACTIONr_gen_planes_refined0.0220.023251
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.4470.22802
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3740.23016
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.3560.2264
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3190.210
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1470.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2411.52703
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.0624372
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.43931760
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.1844.51671
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.5→3.59 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.278 26
Rwork0.279 589

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