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- PDB-5x2a: Crystal structure of EGFR 696-1022 T790M/V948R in complex with SKLB(3) -

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Basic information

Entry
Database: PDB / ID: 5x2a
TitleCrystal structure of EGFR 696-1022 T790M/V948R in complex with SKLB(3)
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M / V948R / SKLB
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / 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 ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / 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 / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / 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 / 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 / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / 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 / ossification / SHC1 events in ERBB2 signaling / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / EGFR downregulation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / cell-cell adhesion / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / negative regulation of protein catabolic process / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / positive regulation of fibroblast proliferation / cell morphogenesis / neuron differentiation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Cargo recognition for clathrin-mediated endocytosis / PIP3 activates AKT signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / virus receptor activity / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade
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-7XO / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.85 Å
AuthorsYun, C.H.
Funding support China, 3items
OrganizationGrant numberCountry
National Science Foundation of China31270769 China
National Basic Research Program of China2012CB917202 China
Ministry of Science and Technology of ChinaNCET-12-0013 China
CitationJournal: Oncotarget / Year: 2018
Title: Structural insights into drug development strategy targeting EGFR T790M/C797S.
Authors: Zhu, S.J. / Zhao, P. / Yang, J. / Ma, R. / Yan, X.E. / Yang, S.Y. / Yang, J.W. / Yun, C.H.
History
DepositionJan 31, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 7, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: 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.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Apr 11, 2018Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / citation ...chem_comp / citation / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _citation.journal_volume ..._chem_comp.name / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.3Mar 20, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_struct_conn_angle / struct_conn
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)154,62227
Polymers150,8984
Non-polymers3,72423
Water18,0691003
1
A: Epidermal growth factor receptor
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,32314
Polymers75,4492
Non-polymers1,87412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5720 Å2
ΔGint-61 kcal/mol
Surface area25650 Å2
MethodPISA
2
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,29913
Polymers75,4492
Non-polymers1,85011
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5990 Å2
ΔGint-16 kcal/mol
Surface area27150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.185, 103.973, 87.150
Angle α, β, γ (deg.)90.00, 101.40, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 37724.598 Da / Num. of mol.: 4 / Fragment: UNP RESIDUES 696-1022 / Mutation: T790M, V948R
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

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Non-polymers , 6 types, 1026 molecules

#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-7XO / N2-[4-(4-methylpiperazin-1-yl)phenyl]-N8-phenyl-9-propan-2-yl-purine-2,8-diamine


Mass: 442.559 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C25H30N8
#5: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#6: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1003 / Source method: isolated from a natural source / Formula: H2O

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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: 2.23 Å3/Da / Density % sol: 44.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1M Bis-Tris 5.0, 22.5% PEG 3350, 5mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97924 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 6, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97924 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 105418 / % possible obs: 98 % / Redundancy: 3.5 % / Net I/σ(I): 14.6

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementResolution: 1.85→39.487 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.78
RfactorNum. reflection% reflection
Rfree0.2194 5277 5.02 %
Rwork0.1735 --
obs0.1758 105211 97.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.85→39.487 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9735 0 208 1003 10946
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.02310329
X-RAY DIFFRACTIONf_angle_d1.8913998
X-RAY DIFFRACTIONf_dihedral_angle_d17.2323974
X-RAY DIFFRACTIONf_chiral_restr0.141554
X-RAY DIFFRACTIONf_plane_restr0.0111748
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.8710.33241710.25053206X-RAY DIFFRACTION97
1.871-1.8930.30671850.23473301X-RAY DIFFRACTION96
1.893-1.91610.2811630.23343258X-RAY DIFFRACTION96
1.9161-1.94040.26321610.21663270X-RAY DIFFRACTION96
1.9404-1.96590.29591770.21373296X-RAY DIFFRACTION97
1.9659-1.99280.27591810.22053252X-RAY DIFFRACTION97
1.9928-2.02130.28371670.21383288X-RAY DIFFRACTION97
2.0213-2.05150.27651590.19733277X-RAY DIFFRACTION97
2.0515-2.08350.23711720.19343292X-RAY DIFFRACTION97
2.0835-2.11770.22852000.18483289X-RAY DIFFRACTION97
2.1177-2.15420.25571840.18513232X-RAY DIFFRACTION97
2.1542-2.19340.26371750.17793313X-RAY DIFFRACTION97
2.1934-2.23560.24751690.17583308X-RAY DIFFRACTION97
2.2356-2.28120.26191670.18693295X-RAY DIFFRACTION98
2.2812-2.33080.25741850.18443355X-RAY DIFFRACTION98
2.3308-2.3850.2391790.1823312X-RAY DIFFRACTION98
2.385-2.44460.22381940.183314X-RAY DIFFRACTION99
2.4446-2.51070.24451910.17583345X-RAY DIFFRACTION99
2.5107-2.58460.22481950.17843371X-RAY DIFFRACTION99
2.5846-2.6680.24151820.1773352X-RAY DIFFRACTION99
2.668-2.76330.22241780.18053380X-RAY DIFFRACTION99
2.7633-2.87390.2481750.18023388X-RAY DIFFRACTION99
2.8739-3.00470.21331730.17673406X-RAY DIFFRACTION99
3.0047-3.1630.22811850.1783377X-RAY DIFFRACTION99
3.163-3.36110.2181670.16773376X-RAY DIFFRACTION100
3.3611-3.62050.19591690.15873426X-RAY DIFFRACTION99
3.6205-3.98450.18061800.14543389X-RAY DIFFRACTION99
3.9845-4.56030.15331740.13433396X-RAY DIFFRACTION99
4.5603-5.74270.17881510.15443450X-RAY DIFFRACTION99
5.7427-39.49590.19531680.18323420X-RAY DIFFRACTION97

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