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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


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Developmental Lineage of Mammary Gland Myoepithelial Cells / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Developmental Lineage of Mammary Gland Myoepithelial Cells / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / ubiquitin-dependent endocytosis / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / Signaling by EGFR / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / intracellular vesicle / eyelid development in camera-type eye / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / protein insertion into membrane / negative regulation of epidermal growth factor receptor signaling pathway / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / embryonic placenta development / xenobiotic transport / salivary gland morphogenesis / positive regulation of epidermal growth factor receptor signaling pathway / sperm end piece / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / sperm principal piece / cellular response to epidermal growth factor stimulus / basal plasma membrane / epithelial cell proliferation / positive regulation of DNA replication / positive regulation of DNA repair / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / cellular response to amino acid stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / cell-cell adhesion / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / epidermal growth factor receptor signaling pathway / kinase binding / Downregulation of ERBB2 signaling / ruffle membrane / positive regulation of fibroblast proliferation / cell morphogenesis / positive regulation of protein phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / neuron differentiation / HCMV Early Events / actin filament binding / transmembrane signaling receptor activity / cell junction / positive regulation of canonical Wnt signaling pathway / sperm midpiece / PIP3 activates AKT signaling / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / positive regulation of cell growth / RAF/MAP kinase cascade / protein tyrosine kinase activity / double-stranded DNA binding / early endosome 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
Revision 1.4Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
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


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