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- PDB-6bgt: Structure of Trastuzumab Fab mutant in complex with Her2 extracel... -

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Basic information

Entry
Database: PDB / ID: 6bgt
TitleStructure of Trastuzumab Fab mutant in complex with Her2 extracellular domain
Components
  • Herceptin heavy chain Fab fragment mutant
  • Herceptin light chain mutant
  • Receptor tyrosine-protein kinase erbB-2
KeywordsTRANSFERASE/IMMUNE SYSTEM / Herceptin / antibody / TRANSFERASE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / motor neuron axon guidance ...negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse / PLCG1 events in ERBB2 signaling / immunoglobulin complex / ERBB2-EGFR signaling pathway / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2 Activates PTK6 Signaling / enzyme-linked receptor protein signaling pathway / neuromuscular junction development / ERBB2-ERBB3 signaling pathway / positive regulation of Rho protein signal transduction / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / positive regulation of transcription by RNA polymerase I / ERBB2 Regulates Cell Motility / oligodendrocyte differentiation / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / regulation of angiogenesis / positive regulation of MAP kinase activity / regulation of ERK1 and ERK2 cascade / Schwann cell development / Downregulation of ERBB2:ERBB3 signaling / coreceptor activity / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / transmembrane receptor protein tyrosine kinase activity / GRB2 events in ERBB2 signaling / positive regulation of cell adhesion / SHC1 events in ERBB2 signaling / basal plasma membrane / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / cellular response to epidermal growth factor stimulus / positive regulation of epithelial cell proliferation / positive regulation of translation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / peptidyl-tyrosine phosphorylation / Signaling by ERBB2 TMD/JMD mutants / Downregulation of ERBB2 signaling / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / receptor tyrosine kinase binding / Signaling by ERBB2 KD Mutants / neuromuscular junction / cellular response to growth factor stimulus / ruffle membrane / epidermal growth factor receptor signaling pathway / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / heart development / presynaptic membrane / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protein tyrosine kinase activity / basolateral plasma membrane / adaptive immune response / early endosome / cell surface receptor signaling pathway / cell population proliferation / endosome membrane / receptor complex / positive regulation of MAPK cascade / intracellular signal transduction / protein phosphorylation / apical plasma membrane / protein heterodimerization activity / signaling receptor binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / extracellular region / nucleoplasm / ATP binding / identical protein binding / nucleus
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 ...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 / : / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Immunoglobulins / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2 / Immunoglobulin gamma-1 heavy chain / Ig-like domain-containing protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsChristie, M. / Christ, D.
Funding support Australia, 2items
OrganizationGrant numberCountry
Australian Research Council (ARC)DE160100608 Australia
Australian Research Council (ARC)DP160104915 Australia
CitationJournal: To Be Published
Title: Stable human IgG antibody therapeutics with native framework structure
Authors: Christie, M. / Rouet, R. / Nevoltris, D. / Langley, D. / Schofield, P. / Fabri, L. / Tingly, K. / Lowe, D. / Jermutus, L. / Christ, D.
History
DepositionOct 29, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Receptor tyrosine-protein kinase erbB-2
A: Herceptin light chain mutant
B: Herceptin heavy chain Fab fragment mutant
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,9184
Polymers120,6973
Non-polymers2211
Water52229
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5650 Å2
ΔGint-27 kcal/mol
Surface area46100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.860, 114.460, 204.279
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Receptor tyrosine-protein kinase erbB-2 / Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / ...Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / Tyrosine kinase-type cell surface receptor HER2 / p185erbB2


Mass: 72499.469 Da / Num. of mol.: 1 / Fragment: UNP residues 1-652
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB2, HER2, MLN19, NEU, NGL / Production host: Homo sapiens (human)
References: UniProt: P04626, receptor protein-tyrosine kinase
#2: Antibody Herceptin light chain mutant


Mass: 23494.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: Q7Z3Y4
#3: Antibody Herceptin heavy chain Fab fragment mutant


Mass: 24703.500 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: P0DOX5
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / Source method: isolated from a natural source / Formula: H2O
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: 3.04 Å3/Da / Density % sol: 59.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 100 mM MES, pH 6.5, 18% PEG3350, 10% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9536 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 11, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9536 Å / Relative weight: 1
ReflectionResolution: 2.7→53.2 Å / Num. obs: 41043 / % possible obs: 99 % / Redundancy: 10.1 % / CC1/2: 0.998 / Net I/σ(I): 12.7
Reflection shellResolution: 2.7→2.81 Å / CC1/2: 0.909

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1N8Z

1n8z


Resolution: 2.7→49.927 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 26.57 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2475 2007 4.9 %RANDOM
Rwork0.205 ---
obs0.207 40965 98.96 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.7→49.927 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7763 0 14 29 7806
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0057991
X-RAY DIFFRACTIONf_angle_d0.83110897
X-RAY DIFFRACTIONf_dihedral_angle_d17.3134835
X-RAY DIFFRACTIONf_chiral_restr0.0511207
X-RAY DIFFRACTIONf_plane_restr0.0061420
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.76750.32551260.26452399X-RAY DIFFRACTION87
2.7675-2.84240.29481260.26342747X-RAY DIFFRACTION98
2.8424-2.9260.30931530.26592756X-RAY DIFFRACTION100
2.926-3.02040.32821510.26372772X-RAY DIFFRACTION100
3.0204-3.12840.2931600.24152755X-RAY DIFFRACTION100
3.1284-3.25360.31161390.2262771X-RAY DIFFRACTION100
3.2536-3.40160.26911480.2252779X-RAY DIFFRACTION100
3.4016-3.58090.25651280.21942811X-RAY DIFFRACTION100
3.5809-3.80520.22781270.19572819X-RAY DIFFRACTION100
3.8052-4.09890.21171400.17732815X-RAY DIFFRACTION100
4.0989-4.51110.1861410.1572838X-RAY DIFFRACTION100
4.5111-5.16330.20271670.15522802X-RAY DIFFRACTION100
5.1633-6.5030.21311420.20382888X-RAY DIFFRACTION100
6.503-49.93540.2831590.22433006X-RAY DIFFRACTION100
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)
11.2161-0.30810.29450.4410.02540.7284-0.02310.00880.08620.08820.1127-0.0154-0.01530.00420.0390.164-0.0176-0.03380.1496-0.00480.2369-0.822728.175-48.6228
21.41810.3331.10120.6882-0.19441.7178-0.2236-0.20270.43320.41120.08010.3087-0.8024-0.1897-0.06050.93360.06570.02360.4893-0.06420.49237.494253.13013.9364
31.75490.39890.57291.20920.07731.6937-0.31610.37960.708-0.15880.22970.426-0.59920.16290.00090.7138-0.0161-0.04090.53810.10940.547630.384550.7722-13.7082
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'C' and resid 1 through 607)
2X-RAY DIFFRACTION2(chain 'A' and resid 1 through 211)
3X-RAY DIFFRACTION3(chain 'B' and resid 1 through 220)

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