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- PDB-4leo: Crystal structure of anti-HER3 Fab RG7116 in complex with the ext... -

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Basic information

Entry
Database: PDB / ID: 4leo
TitleCrystal structure of anti-HER3 Fab RG7116 in complex with the extracellular domains of human Her3 (ERBB3)
Components
  • RG7116 Fab heavy chain
  • RG7116 Fab light chain
  • Receptor tyrosine-protein kinase erbB-3
KeywordsTransferase/Immune System / Fab fragment / Therapeutic antibody / Her3 receptor / Transferase-Immune System complex
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 / motor neuron apoptotic process / growth factor binding / ERBB2 Activates PTK6 Signaling / ERBB2-ERBB3 signaling pathway / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Signaling by ERBB4 / PI3K events in ERBB2 signaling / lateral plasma membrane / negative regulation of signal transduction / Schwann cell development / Signaling by ERBB2 / extrinsic apoptotic signaling pathway in absence of ligand / myelination / Downregulation of ERBB2:ERBB3 signaling / SHC1 events in ERBB2 signaling / cell surface receptor protein tyrosine kinase signaling pathway / basal plasma membrane / positive regulation of epithelial cell proliferation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / Signaling by ERBB2 TMD/JMD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 KD Mutants / Downregulation of ERBB2 signaling / epidermal growth factor receptor signaling pathway / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / regulation of cell population proliferation / heart development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / neuron apoptotic process / basolateral plasma membrane / negative regulation of neuron apoptotic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / protein kinase activity / positive regulation of MAPK cascade / apical plasma membrane / protein heterodimerization activity / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / signal transduction / extracellular space / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2 / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A, domain 2 / 24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / 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 ...Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2 / Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A, domain 2 / 24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-domain / 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 / : / Ribbon / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-3
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.64 Å
AuthorsSchiller, C.B. / Hopfner, K.P.
CitationJournal: Cancer Res. / Year: 2013
Title: RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation.
Authors: Mirschberger, C. / Schiller, C.B. / Schraml, M. / Dimoudis, N. / Friess, T. / Gerdes, C.A. / Reiff, U. / Lifke, V. / Hoelzlwimmer, G. / Kolm, I. / Hopfner, K.P. / Niederfellner, G. / Bossenmaier, B.
History
DepositionJun 26, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software
Revision 1.3Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _atom_site.occupancy / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_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_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 30, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_unobs_or_zero_occ_atoms
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: RG7116 Fab heavy chain
B: RG7116 Fab light chain
C: Receptor tyrosine-protein kinase erbB-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,5109
Polymers116,9803
Non-polymers1,5306
Water2,702150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.458, 59.359, 103.661
Angle α, β, γ (deg.)97.64, 106.85, 96.83
Int Tables number1
Space group name H-MP1

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Components

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Antibody , 2 types, 2 molecules AB

#1: Antibody RG7116 Fab heavy chain


Mass: 24369.264 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody RG7116 Fab light chain


Mass: 24231.783 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)

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Protein / Non-polymers , 2 types, 151 molecules C

#3: Protein Receptor tyrosine-protein kinase erbB-3 / Her3 (ERBB3) extracellular domains / Proto-oncogene-like protein c-ErbB-3 / Tyrosine kinase-type ...Her3 (ERBB3) extracellular domains / Proto-oncogene-like protein c-ErbB-3 / Tyrosine kinase-type cell surface receptor HER3


Mass: 68378.500 Da / Num. of mol.: 1 / Fragment: UNP residues 20-631
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB3, HER3 / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P21860, receptor protein-tyrosine kinase
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 150 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 2 types, 6 molecules

#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#5: 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.: 5
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

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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: 2.68 Å3/Da / Density % sol: 54.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Potassium sodium tartrate tetrahydrate, 20% w/v Polyethylene glycol 3350 , pH pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K
PH range: pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: May 21, 2012
RadiationMonochromator: Horizontally side diffracting Silicon 111 crystal. Fixed wavelength (0.873)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.64→48.83 Å / Num. all: 35804 / Num. obs: 34229 / % possible obs: 95.6 % / Observed criterion σ(I): -3
Reflection shellResolution: 2.64→2.8 Å / % possible all: 93.8

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Processing

Software
NameVersionClassification
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.64→48.83 Å / SU ML: 0.36 / σ(F): 2 / Phase error: 27.82 / Stereochemistry target values: ML
Details: SEVERAL ATOMS IN NAG C702 HAS BEEN SET TO ZERO OCCUPANCY BY PURPOSE, SINCE THEY ARE NOT COVERED BY THE 2FO-FC DENSITY AT 1.0 ANG SIGMA CONTOUR LEVEL
RfactorNum. reflection% reflectionSelection details
Rfree0.2578 1710 5 %RANDOM
Rwork0.228 ---
obs0.2295 34214 95.83 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.64→48.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7937 0 98 150 8185
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0048259
X-RAY DIFFRACTIONf_angle_d0.76411172
X-RAY DIFFRACTIONf_dihedral_angle_d14.7572970
X-RAY DIFFRACTIONf_chiral_restr0.0541235
X-RAY DIFFRACTIONf_plane_restr0.0041454
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.64-2.7180.34211420.31922686X-RAY DIFFRACTION93
2.718-2.80580.31971410.30052694X-RAY DIFFRACTION96
2.8058-2.9060.33581440.30022716X-RAY DIFFRACTION96
2.906-3.02240.32811410.28322715X-RAY DIFFRACTION95
3.0224-3.15990.28251430.27412701X-RAY DIFFRACTION97
3.1599-3.32640.27491430.25612733X-RAY DIFFRACTION97
3.3264-3.53480.25561450.23272739X-RAY DIFFRACTION97
3.5348-3.80760.26041420.22142711X-RAY DIFFRACTION96
3.8076-4.19060.25831440.20412733X-RAY DIFFRACTION96
4.1906-4.79660.21661400.18112656X-RAY DIFFRACTION96
4.7966-6.04140.22611430.20052722X-RAY DIFFRACTION95
6.0414-48.830.2181420.20482698X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: 19.7348 Å / Origin y: 8.495 Å / Origin z: -20.5218 Å
111213212223313233
T0.4435 Å2-0.0287 Å2-0.0454 Å2-0.2906 Å2-0.0802 Å2--0.2822 Å2
L0.4813 °20.0832 °2-0.1984 °2-0.1959 °2-0.0906 °2--0.2041 °2
S0.0862 Å °-0.0004 Å °0.0208 Å °-0.0132 Å °-0.026 Å °0.0263 Å °0.0633 Å °-0.0047 Å °-0.0542 Å °
Refinement TLS groupSelection details: all

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