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- PDB-5sx5: Crystal Structure of panitumumab in complex with epidermal growth... -

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Basic information

Entry
Database: PDB / ID: 5sx5
TitleCrystal Structure of panitumumab in complex with epidermal growth factor receptor domain 3 mutant S468R.
Components
  • (Panitumumab Fab ...) x 2
  • Epidermal growth factor receptor
KeywordsTRANSFERASE/IMMUNE SYSTEM / Cetuximab / panitumumab / EGFR / Vectibix / Erbitux / TRANSFERASE-IMMUNE SYSTEM complex
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 / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / neuron differentiation / positive regulation of fibroblast proliferation / 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 / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade
Similarity search - Function
24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Alpha-Beta Horseshoe / 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 ...24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Alpha-Beta Horseshoe / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Immunoglobulins / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 Å
AuthorsSickmier, E.A.
CitationJournal: Plos One / Year: 2016
Title: The Panitumumab EGFR Complex Reveals a Binding Mechanism That Overcomes Cetuximab Induced Resistance.
Authors: Sickmier, E.A. / Kurzeja, R.J. / Michelsen, K. / Vazir, M. / Yang, E. / Tasker, A.S.
History
DepositionAug 9, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 5, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 4, 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_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
K: Panitumumab Fab Light Chain
J: Panitumumab Fab Heavy Chain
L: Panitumumab Fab Light Chain
H: Panitumumab Fab Heavy Chain
M: Epidermal growth factor receptor
N: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,23228
Polymers138,8096
Non-polymers2,42222
Water2,504139
1
K: Panitumumab Fab Light Chain
J: Panitumumab Fab Heavy Chain
M: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,24011
Polymers69,4053
Non-polymers8358
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6820 Å2
ΔGint-63 kcal/mol
Surface area26750 Å2
MethodPISA
2
L: Panitumumab Fab Light Chain
H: Panitumumab Fab Heavy Chain
N: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,99217
Polymers69,4053
Non-polymers1,58714
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8400 Å2
ΔGint-125 kcal/mol
Surface area26200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.073, 113.106, 231.403
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules MN

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


Mass: 22350.432 Da / Num. of mol.: 2 / Fragment: UNP residues 335-528
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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Antibody , 2 types, 4 molecules KLJH

#1: Antibody Panitumumab Fab Light Chain


Mass: 23379.875 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody Panitumumab Fab Heavy Chain


Mass: 23674.430 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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Non-polymers , 5 types, 161 molecules

#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 139 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 3.07 Å3/Da / Density % sol: 59.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 2.0 M AmSO4, 100 mM MES 6.5 and 5% peg 400

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→30 Å / Num. obs: 58643 / % possible obs: 97.6 % / Redundancy: 4.1 % / Biso Wilson estimate: 38.26 Å2 / Rmerge(I) obs: 0.046 / Rpim(I) all: 0.026 / Rrim(I) all: 0.053 / Χ2: 0.891 / Net I/av σ(I): 25.056 / Net I/σ(I): 14.2 / Num. measured all: 239127
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.5-2.593.80.453192
2.59-2.693.80.327192.8
2.69-2.823.80.219194.4
2.82-2.963.80.153197.5
2.96-3.153.90.106199.6
3.15-3.394.10.07199.9
3.39-3.734.40.0511100
3.73-4.274.50.0431100
4.27-5.384.40.0411100
5.38-304.20.022199.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
PHASERphasing
PHENIXdev_2356refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1yy9

1yy9


Resolution: 2.5→29.979 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.74
RfactorNum. reflection% reflection
Rfree0.2498 2686 4.88 %
Rwork0.2257 --
obs0.2269 55059 91.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 224.36 Å2 / Biso mean: 55.5934 Å2 / Biso min: 13.75 Å2
Refinement stepCycle: final / Resolution: 2.5→29.979 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9361 0 144 139 9644
Biso mean--69.19 35.05 -
Num. residues----1225
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029701
X-RAY DIFFRACTIONf_angle_d0.49513164
X-RAY DIFFRACTIONf_chiral_restr0.0431489
X-RAY DIFFRACTIONf_plane_restr0.0041660
X-RAY DIFFRACTIONf_dihedral_angle_d11.8395780
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 19

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5001-2.54560.3405960.30041826192263
2.5456-2.59450.32691090.30122004211368
2.5945-2.64740.2971200.28982187230774
2.6474-2.7050.30131360.30022259239576
2.705-2.76780.32961360.27432459259584
2.7678-2.8370.29731280.28432630275888
2.837-2.91360.31911440.2852785292995
2.9136-2.99930.29721450.28282897304298
2.9993-3.0960.27291430.285730103153100
3.096-3.20660.27331450.250329573102100
3.2066-3.33480.29391390.255629943133100
3.3348-3.48630.25781510.252529733124100
3.4863-3.66980.25851470.233130223169100
3.6698-3.89930.26841320.21730163148100
3.8993-4.19960.21051630.192130133176100
4.1996-4.62090.18871530.163730203173100
4.6209-5.28640.22581470.168330533200100
5.2864-6.64830.21231630.230873250100
6.6483-29.98070.22131890.20373181337099
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)
11.67540.1589-0.67150.6046-1.22663.9762-0.3068-0.10040.1290.88780.18850.6285-0.2583-0.47780.02570.55120.11530.23880.27-0.03160.45427.64325.85537.6135
21.5067-0.09990.37231.06790.58013.2023-0.3083-0.0674-0.25151.15980.2538-0.70370.48560.3997-0.03160.73220.1559-0.21940.2478-0.01360.50851.5858-23.38637.4153
33.332-0.3268-0.7443.2006-0.01413.7337-0.08410.11230.08920.56490.0105-0.1298-0.20480.08040.07440.32340.0339-0.08890.1236-0.01790.2311-8.4916-4.446831.359
42.85550.31751.40322.75130.66383.82520.0716-0.0023-0.16720.4712-0.03840.27760.3345-0.0461-0.02410.3220.03280.1260.15420.00930.255237.04376.435631.9912
51.2890.0681-0.30732.10390.12240.3578-0.5878-0.77990.40361.56250.3698-0.1490.53840.24940.1212.07120.4066-0.37140.4186-0.14630.5068-1.2661-10.951864.3195
62.38730.28550.49511.397-0.03990.1246-0.4727-1.1159-0.43020.79830.2903-0.3211-0.0142-0.09360.20991.76550.15610.46230.53420.20330.427432.943315.893165.0074
71.525-0.00440.17162.6548-0.55651.9770.07580.61450.0482-0.13820.0105-0.05760.10230.0298-0.07330.10310.0015-0.05290.64-0.01770.371331.141519.0182-2.267
83.8323-0.0022-0.97222.6458-0.33162.0936-0.13320.4794-0.02910.12890.0545-0.2187-0.02490.43190.07490.10190.00180.05960.6563-0.14830.4657.646-23.89967.856
91.488-0.173-0.24211.61980.06741.37190.05020.8122-0.1773-0.1611-0.02680.1294-0.13230.0308-0.04190.1063-0.00370.07120.7884-0.11160.4198-4.2351-19.253-2.8009
102.77820.2540.55261.8796-0.10741.4952-0.16240.2898-0.07580.09660.04690.21840.024-0.51070.10510.033-0.0105-0.03290.60990.01720.482319.306824.44498.0699
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'H' and ((resseq 1:119))H1 - 119
2X-RAY DIFFRACTION2chain 'J' and ((resseq 1:119))J1 - 119
3X-RAY DIFFRACTION3chain 'K' and ((resseq 1:107))K1 - 107
4X-RAY DIFFRACTION4chain 'L' and ((resseq 1:107))L1 - 107
5X-RAY DIFFRACTION5chain 'M' and ((resseq 310:501))M310 - 501
6X-RAY DIFFRACTION6chain 'N' and ((resseq 310:501))N310 - 501
7X-RAY DIFFRACTION7chain 'L' and ((resseq 108:212))L108 - 212
8X-RAY DIFFRACTION8chain 'J' and ((resseq 120:218))J120 - 218
9X-RAY DIFFRACTION9chain 'K' and ((resseq 108:213))K108 - 213
10X-RAY DIFFRACTION10chain 'H' and ((resseq 120:218))H120 - 218

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