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- PDB-5sx4: Crystal Structure of panitumumab in complex with epidermal growth... -

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Basic information

Entry
Database: PDB / ID: 5sx4
TitleCrystal Structure of panitumumab in complex with epidermal growth factor receptor domain 3.
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 / 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 / sperm principal piece / ossification / basal plasma membrane / cellular response to epidermal growth factor stimulus / 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 / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to estradiol stimulus / cellular response to amino acid stimulus / clathrin-coated endocytic vesicle membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / 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
24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / Alpha-Beta Horseshoe / : / 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 ...24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / Alpha-Beta Horseshoe / : / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulins / Protein kinase domain profile. / Protein kinase domain / 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 / Resolution: 2.8 Å
AuthorsSickmier, E.A. / Kurzeja, R.J.M. / Michelsen, K. / Mukta, V. / Yang, E. / Tasker, A.S.
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 1.2Oct 16, 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
I: 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)140,06818
Polymers138,6696
Non-polymers1,39912
Water2,108117
1
I: Panitumumab Fab Light Chain
J: Panitumumab Fab Heavy Chain
M: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,9538
Polymers69,3353
Non-polymers6195
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6290 Å2
ΔGint-67 kcal/mol
Surface area26580 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)70,11510
Polymers69,3353
Non-polymers7817
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6650 Å2
ΔGint-81 kcal/mol
Surface area27060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.273, 113.184, 232.443
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: 22280.316 Da / Num. of mol.: 2 / Fragment: UNP residues 335-525
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 ILJH

#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, 129 molecules

#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#7: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / 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: 3.1 Å3/Da / Density % sol: 60.27 %
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: May 17, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 43522 / % possible obs: 99.6 % / Redundancy: 6 % / Biso Wilson estimate: 36.13 Å2 / Rmerge(I) obs: 0.098 / Χ2: 0.95 / Net I/av σ(I): 14.637 / Net I/σ(I): 13.4 / Num. measured all: 261344
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.8-2.95.20.502198.6
2.9-3.025.30.333198.9
3.02-3.155.40.235199.3
3.15-3.325.50.169199.7
3.32-3.535.70.144199.9
3.53-3.860.128199.9
3.8-4.186.40.1171100
4.18-4.786.80.1041100
4.78-6.026.80.0871100
6.02-306.70.057199.7

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHENIXdev_2356refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YY9

1yy9


Resolution: 2.8→29.596 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.01
RfactorNum. reflection% reflection
Rfree0.2661 1974 5.05 %
Rwork0.2233 --
obs0.2255 39087 88.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 148.15 Å2 / Biso mean: 54.6188 Å2 / Biso min: 8.95 Å2
Refinement stepCycle: final / Resolution: 2.8→29.596 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9305 0 82 117 9504
Biso mean--70.32 32.08 -
Num. residues----1218
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029592
X-RAY DIFFRACTIONf_angle_d0.48513034
X-RAY DIFFRACTIONf_chiral_restr0.0431484
X-RAY DIFFRACTIONf_plane_restr0.0041650
X-RAY DIFFRACTIONf_dihedral_angle_d11.3355739
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8-2.84730.3786510.3161120117137
2.8473-2.92420.37341070.29081857196464
2.9242-3.01020.35271010.30122122222371
3.0102-3.10720.33621440.28392353249779
3.1072-3.21820.32781280.26132640276889
3.2182-3.34680.26211620.2582842300496
3.3468-3.49890.30541770.25422925310299
3.4989-3.68310.31611630.24982970313399
3.6831-3.91340.29391520.232984313699
3.9134-4.21470.29171500.19812991314199
4.2147-4.63740.19271390.16723003314299
4.6374-5.30510.20251510.168230413192100
5.3051-6.67120.23341620.210430843246100
6.6712-29.59810.20511870.21513181336899
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)
11.52540.6965-0.04970.9229-0.06372.9175-0.0218-0.116-0.146-0.5185-0.0349-0.07490.16690.14650.03650.4083-0.00110.03440.1092-0.03160.208224.21124.5752-31.5154
21.15110.03780.48882.14440.84042.9711-0.30470.10160.1911-0.81580.0554-0.6351-0.30830.38170.15320.6507-0.10070.15740.2130.00230.388334.388423.5384-37.6645
31.91160.5568-0.41211.22690.2042.56750.0914-0.10770.2876-0.1856-0.10520.2097-0.3759-0.0580.01470.41270.0088-0.14670.1449-0.01260.252569.5556-6.2319-32.0136
40.7984-0.2339-0.06271.0063-0.89942.7139-0.32730.141-0.0386-0.63420.03760.62190.0614-0.49030.090.4804-0.0595-0.25110.2784-0.02680.393460.0927-25.6849-37.8348
50.547-0.0328-0.11181.11710.22870.6734-0.41450.633-0.2086-0.92370.2333-0.0049-0.21720.14970.13521.8961-0.26370.23150.4462-0.07310.482531.114711.352-64.6608
60.787-0.07150.11130.5526-0.22870.5557-0.1830.74540.2352-0.54340.0683-0.1657-0.0673-0.04850.06831.6511-0.2328-0.47220.57320.18720.305965.8831-15.6354-65.2084
71.27870.03050.26991.33370.30411.20190.0607-0.5220.17560.01040.03480.13810.1869-0.1728-0.0556-0.16270.0249-0.19590.9017-0.14090.263828.785519.16582.4757
82.78530.15580.14721.483-0.0971.2253-0.0564-0.1739-0.00360.0435-0.0418-0.22310.05930.37150.0732-0.0431-0.024-0.12090.6266-0.27070.459240.843524.1875-8.2923
92.9597-0.22090.14321.4653-0.0771.4845-0.1366-0.36740.17230.0961-0.09340.1498-0.2448-0.39560.067-0.0688-0.00860.07030.6781-0.01860.425351.5856-23.9239-7.6163
101.7880.0398-0.33061.6741-0.41961.36560.0137-0.4194-0.06360.04790.009-0.1311-0.21790.0367-0.03760.0768-0.02110.04190.608-0.06460.369563.6313-19.04992.2589
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'I' and resid 1 through 107)I1 - 107
2X-RAY DIFFRACTION2(chain 'J' and resid 1 through 119)J1 - 119
3X-RAY DIFFRACTION3(chain 'L' and resid 1 through 107)L1 - 107
4X-RAY DIFFRACTION4(chain 'H' and resid 1 through 119)H1 - 119
5X-RAY DIFFRACTION5(chain 'M' and resid 312 through 502)M312 - 502
6X-RAY DIFFRACTION6(chain 'N' and resid 310 through 501)N310 - 501
7X-RAY DIFFRACTION7(chain 'I' and resid 108 through 211)I108 - 211
8X-RAY DIFFRACTION8(chain 'J' and resid 120 through 218)J120 - 218
9X-RAY DIFFRACTION9(chain 'H' and resid 120 through 218)H120 - 218
10X-RAY DIFFRACTION10(chain 'L' and resid 108 through 212)L108 - 212

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