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- PDB-4rix: Crystal structure of an EGFR/HER3 kinase domain heterodimer conta... -

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Basic information

Entry
Database: PDB / ID: 4rix
TitleCrystal structure of an EGFR/HER3 kinase domain heterodimer containing the cancer-associated HER3-Q790R mutation
Components
  • Epidermal growth factor receptor
  • Receptor tyrosine-protein kinase erbB-3
KeywordsTRANSFERASE / RECEPTOR TYROSINE KINASE / PSEUDOKINASE / KINASE / ATP BINDING / MEMBRANE
Function / homology
Function and homology information


neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / ERBB3:ERBB2 complex / GRB7 events in ERBB2 signaling / positive regulation of calcineurin-NFAT signaling cascade ...neuregulin binding / positive regulation of cardiac muscle tissue development / cranial nerve development / Schwann cell differentiation / neuregulin receptor activity / negative regulation of secretion / endocardial cushion development / ERBB3:ERBB2 complex / GRB7 events in ERBB2 signaling / positive regulation of calcineurin-NFAT signaling cascade / peripheral nervous system development / ErbB-3 class receptor binding / negative regulation of cell adhesion / negative regulation of motor neuron apoptotic process / 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 / motor neuron apoptotic process / 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 / ERBB2-ERBB3 signaling pathway / protein tyrosine kinase activator activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signaling by ERBB4 / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / growth factor binding / 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 / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / lateral plasma membrane / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / Schwann cell development / salivary gland morphogenesis / negative regulation of signal transduction / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of phosphorylation / positive regulation of vasoconstriction / Signaling by ERBB2 / extrinsic apoptotic signaling pathway in absence of ligand / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / positive regulation of DNA repair / myelination / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / Downregulation of ERBB2:ERBB3 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / epithelial cell proliferation / positive regulation of DNA replication
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
ADENOSINE-5'-DIPHOSPHATE / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Epidermal growth factor receptor / Receptor tyrosine-protein kinase erbB-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsLittlefield, P. / Liu, L. / Jura, N.
CitationJournal: Sci.Signal. / Year: 2014
Title: Structural analysis of the EGFR/HER3 heterodimer reveals the molecular basis for activating HER3 mutations.
Authors: Littlefield, P. / Liu, L. / Mysore, V. / Shan, Y. / Shaw, D.E. / Jura, N.
History
DepositionOct 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 10, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 17, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ncs_dom_lim / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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_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_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase erbB-3
B: Epidermal growth factor receptor
C: Receptor tyrosine-protein kinase erbB-3
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)153,33712
Polymers151,3734
Non-polymers1,9648
Water0
1
A: Receptor tyrosine-protein kinase erbB-3
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,6686
Polymers75,6862
Non-polymers9824
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4720 Å2
ΔGint-44 kcal/mol
Surface area24850 Å2
MethodPISA
2
C: Receptor tyrosine-protein kinase erbB-3
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,6686
Polymers75,6862
Non-polymers9824
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4900 Å2
ΔGint-47 kcal/mol
Surface area25280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.649, 155.053, 86.857
Angle α, β, γ (deg.)90.00, 111.09, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain C
12chain B
22chain D

NCS domain segments:

Component-ID: 1

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11VALVALLYSLYSchain AAA680 - 9605 - 285
21VALVALLYSLYSchain CCC680 - 9605 - 285
12LEULEUASPASPchain BBB664 - 96011 - 307
22LEULEUASPASPchain DDD664 - 96011 - 307

NCS ensembles :
ID
1
2

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Components

#1: Protein Receptor tyrosine-protein kinase erbB-3 / Proto-oncogene-like protein c-ErbB-3 / Tyrosine kinase-type cell surface receptor HER3


Mass: 36519.215 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, UNP residues 698-1020 / Mutation: Q790R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB3, HER3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P21860, receptor protein-tyrosine kinase
#2: Protein Epidermal growth factor receptor / / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 39167.219 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, UNP residues 682-1022 / Mutation: V924R, F973A, L977A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE / Adenosine diphosphate


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM

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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: 2.71 Å3/Da / Density % sol: 54.6 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10 mg/mL protein, 0.1M HEPES pH 7.5, 15% PEG-5000 MME, 5mM magnesium chloride, 0.5M ammonium acetate, 2mM AMP-PNP, 1mM TCEP, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.115867 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 27, 2014
RadiationMonochromator: KHOZU DOUBLE FLAT CRYSTAL, SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.115867 Å / Relative weight: 1
ReflectionResolution: 3.1→59.77 Å / Num. all: 28835 / Num. obs: 27509 / % possible obs: 95.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 1.7 % / Rmerge(I) obs: 0.173 / Net I/σ(I): 6.9
Reflection shellResolution: 3.1→3.27 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.587 / Mean I/σ(I) obs: 2.4 / % possible all: 96.8

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
PHENIX(phenix.refine: 1.9_1692)refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GS6 AND 3KEX

2gs6

3kex


Resolution: 3.1→59.77 Å / SU ML: 0.39 / σ(F): 1.33 / Phase error: 28.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.258 1387 5.04 %
Rwork0.207 --
obs0.2096 27509 94.99 %
all-28835 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.1→59.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9027 0 120 0 9147
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0069359
X-RAY DIFFRACTIONf_angle_d1.20612705
X-RAY DIFFRACTIONf_dihedral_angle_d15.9493514
X-RAY DIFFRACTIONf_chiral_restr0.051430
X-RAY DIFFRACTIONf_plane_restr0.0061575
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2332X-RAY DIFFRACTION8.677TORSIONAL
12C2332X-RAY DIFFRACTION8.677TORSIONAL
21B2582X-RAY DIFFRACTION8.677TORSIONAL
22D2582X-RAY DIFFRACTION8.677TORSIONAL
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1-3.21080.34021310.27952647X-RAY DIFFRACTION97
3.2108-3.33930.31381460.26452618X-RAY DIFFRACTION96
3.3393-3.49130.31551310.24722661X-RAY DIFFRACTION96
3.4913-3.67530.2851310.21782615X-RAY DIFFRACTION96
3.6753-3.90560.27731590.20662601X-RAY DIFFRACTION96
3.9056-4.20710.24871370.19592617X-RAY DIFFRACTION95
4.2071-4.63030.20461360.17242608X-RAY DIFFRACTION95
4.6303-5.29990.23451320.18432616X-RAY DIFFRACTION95
5.2999-6.6760.27871410.2042585X-RAY DIFFRACTION93
6.676-59.78290.20821430.192554X-RAY DIFFRACTION92
Refinement TLS params.

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)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.5210.2490.74341.4658-0.05161.1576-0.0965-0.2887-0.03040.20090.09740.21210.0033-0.36560.0010.5773-0.04770.01450.48260.070.48468.2226-57.525828.5376
21.19030.3315-0.64354.5984-0.90794.0415-0.0407-0.0908-0.1720.08770.0706-0.12180.16020.0363-0.00210.23880.0649-0.00830.3315-0.01030.266610.7842-35.620614.9773
31.08060.79310.58213.389-0.23753.5292-0.0042-0.20820.0078-0.2116-0.1288-0.0495-0.1345-0.10210.00190.37220.03190.06050.34560.00310.38812.9679-12.94458.7517
42.1664-0.1832-0.44464.026-1.29992.47180.11620.07390.0959-0.2322-0.03750.1415-0.1084-0.1807-0.00030.34520.0601-0.01490.3516-0.0120.24741.0731.2027-8.8111
51.57791.1326-0.26413.5899-0.92731.0872-0.06290.26780.3215-0.43540.11370.0733-0.15860.0805-0.00020.32050.0065-0.00340.37060.02130.33737.350127.0295-51.0025
61.59080.0767-0.99663.84740.4294.3679-0.0973-0.0463-0.099-0.05070.0475-0.32990.29590.2350.01260.2110.02230.00310.30610.0140.294736.01976.407-43.4637
72.2715-0.2231-1.20513.6108-0.94772.5817-0.0224-0.0665-0.1823-0.3779-0.1204-0.10850.2066-0.06540.00240.4692-0.00470.04240.385-0.03770.39931.1995-11.8079-38.0004
83.29030.6298-0.17323.4675-0.47112.6910.10060.2240.2004-0.0851-0.08030.21840.1457-0.14110.00140.3719-0.02360.03580.3114-0.01020.316910.706-25.7632-33.1418
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 680:775)
2X-RAY DIFFRACTION2(chain A and resid 776:960)
3X-RAY DIFFRACTION3(chain B and resid 664:773)
4X-RAY DIFFRACTION4(chain B and resid 774:960)
5X-RAY DIFFRACTION5(chain C and resid 680:844)
6X-RAY DIFFRACTION6(chain C and resid 845:960)
7X-RAY DIFFRACTION7(chain D and resid 664:773)
8X-RAY DIFFRACTION8(chain D and resid 774:960)

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