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- PDB-1n8z: Crystal structure of extracellular domain of human HER2 complexed... -

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Basic information

Entry
Database: PDB / ID: 1n8z
TitleCrystal structure of extracellular domain of human HER2 complexed with Herceptin Fab
Components
  • (Herceptin Fab (antibody) - ...) x 2
  • Receptor protein-tyrosine kinase erbB-2
KeywordsTRANSFERASE / tyrosin kinase receptor / cell surface receptor
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 / regulation of microtubule-based process / ErbB-3 class receptor binding / semaphorin receptor complex / Sema4D induced cell migration and growth-cone collapse ...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 / regulation of microtubule-based process / ErbB-3 class receptor binding / semaphorin receptor complex / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / neuromuscular junction development / positive regulation of Rho protein signal transduction / ERBB2 Activates PTK6 Signaling / 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 / enzyme-linked receptor protein signaling pathway / positive regulation of transcription by RNA polymerase I / ERBB2-ERBB3 signaling pathway / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of cell adhesion / positive regulation of protein targeting to membrane / regulation of angiogenesis / coreceptor activity / Schwann cell development / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / myelination / Downregulation of ERBB2:ERBB3 signaling / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / neurogenesis / basal plasma membrane / regulation of ERK1 and ERK2 cascade / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of translation / positive regulation of epithelial cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / wound healing / neuromuscular junction / Signaling by ERBB2 ECD mutants / neuron differentiation / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / cellular response to growth factor stimulus / Downregulation of ERBB2 signaling / ruffle membrane / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / presynaptic membrane / heart development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / basolateral plasma membrane / protein tyrosine kinase activity / positive regulation of MAPK cascade / early endosome / cell surface receptor signaling pathway / receptor complex / endosome membrane / intracellular signal transduction / apical plasma membrane / positive regulation of protein phosphorylation / protein heterodimerization activity / protein phosphorylation / signaling receptor binding / positive regulation of cell population proliferation / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / membrane / identical protein binding / nucleus / plasma membrane
Similarity search - Function
24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-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 / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Alpha-Beta Horseshoe ...24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A / Receptor L-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 / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Alpha-Beta Horseshoe / 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 / 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 / Immunoglobulins / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 Å
AuthorsCho, H.-S. / Mason, K. / Ramyar, K.X. / Stanley, A.M. / Gabelli, S.B. / Denney Jr., D.W. / Leahy, D.J.
CitationJournal: Nature / Year: 2003
Title: Structure of the Extracellular Region of HER2 Alone and in Complex with the Herceptin Fab
Authors: Cho, H.-S. / Mason, K. / Ramyar, K.X. / Stanley, A.M. / Gabelli, S.B. / Denney Jr., D.W. / Leahy, D.J.
History
DepositionNov 21, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 18, 2003Provider: repository / Type: Initial release
Revision 1.1May 5, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Feb 5, 2014Group: Source and taxonomy
Revision 1.4Jul 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_leaving_atom_flag / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Aug 16, 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
Remark 999SEQUENCE The sequences of Herseptin Fab light chain (molecule A) and heavy chain (molecule B) were ...SEQUENCE The sequences of Herseptin Fab light chain (molecule A) and heavy chain (molecule B) were not deposited into any database.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)114,4196
Polymers113,8803
Non-polymers5383
Water1,42379
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.17, 109.770, 175.140
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Antibody , 2 types, 2 molecules AB

#1: Antibody Herceptin Fab (antibody) - light chain


Mass: 23466.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus, Homo sapiens
#2: Antibody Herceptin Fab (antibody) - heavy chain


Mass: 23425.180 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus, Homo sapiens

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Protein / Sugars , 2 types, 3 molecules C

#3: Protein Receptor protein-tyrosine kinase erbB-2 / / Tyrosine kinase-type cell surface receptor HER2


Mass: 66989.109 Da / Num. of mol.: 1 / Fragment: extracellular domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HER2(erbB2) / Plasmid: pSGHV0 / Production host: Cricetulus griseus (Chinese hamster) / Strain (production host): CHO(Lec1) / References: UniProt: P04626, EC: 2.7.1.112
#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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
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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Non-polymers , 2 types, 80 molecules

#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 79 / Source method: isolated from a natural source / Formula: H2O

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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: 2.89 Å3/Da / Density % sol: 57.13 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20-30% PEG 5000 MME, 0.1M MES pH6.5, 0.2M ammonium sulfate, VAPOR DIFFUSION, HANGING DROP, temperature 298K
Crystal grow
*PLUS
pH: 7.5
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
15 mg/mlprotein1drop
210 mMTris1droppH7.5
315-30 %PEG40001reservoir
450 mMsodium citrate1reservoirpH5.4
510 mMEDTA1reservoir

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A
DetectorType: ADSC QUANTUM 4 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.5→20 Å / Num. all: 44400 / Num. obs: 42223 / % possible obs: 96.4 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.9 %
Reflection shellResolution: 2.52→2.58 Å / % possible all: 90
Reflection
*PLUS
Lowest resolution: 30 Å / Num. measured all: 164522 / Rmerge(I) obs: 0.068
Reflection shell
*PLUS
% possible obs: 82.4 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 1.9

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMAC5.1.19refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB 1M6B

1m6b


Resolution: 2.52→20 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.871 / SU B: 13.011 / SU ML: 0.279 / Cross valid method: THROUGHOUT / σ(F): 1 / σ(I): 1 / ESU R: 0.671 / ESU R Free: 0.342
RfactorNum. reflection% reflectionSelection details
Rfree0.28425 1871 4.8 %RANDOM
Rwork0.22205 ---
all0.226 42223 --
obs0.22521 37518 92.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 16.813 Å2
Baniso -1Baniso -2Baniso -3
1--2.69 Å20 Å20 Å2
2---0.37 Å20 Å2
3---3.07 Å2
Refinement stepCycle: LAST / Resolution: 2.52→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7778 0 33 79 7890
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0218023
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7861.95610938
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.71351008
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_chiral_restr0.1110.21216
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.026128
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2480.23505
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1530.2319
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.280.256
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0960.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_mcbond_it0.6541.55057
X-RAY DIFFRACTIONr_mcangle_it1.28328164
X-RAY DIFFRACTIONr_scbond_it2.19332966
X-RAY DIFFRACTIONr_scangle_it3.614.52774
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.521→2.586 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rwork0.336 2058
Rfree-0
Refinement
*PLUS
Lowest resolution: 30 Å / % reflection Rfree: 5 % / Rfactor Rfree: 0.286 / Rfactor Rwork: 0.223
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_d0.016
X-RAY DIFFRACTIONr_angle_d
X-RAY DIFFRACTIONr_angle_deg1.79

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