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- PDB-3pp0: Crystal Structure of the Kinase domain of Human HER2 (erbB2). -

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Basic information

Entry
Database: PDB / ID: 3pp0
TitleCrystal Structure of the Kinase domain of Human HER2 (erbB2).
ComponentsReceptor tyrosine-protein kinase erbB-2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE DOMAIN / ANTI-ONCOGENE / ATP-BINDING / CELL CYCLE / DISEASE MUTATION / GLYCOPROTEIN / MEMBRANE / NUCLEOTIDE-BINDING / PHOSPHOPROTEIN / RECEPTOR / SECRETED / TRANSFERASE / TRANSMEMBRANE / TYROSINE-PROTEIN KINASE / TYROSINE KINASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR 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 / 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 / neuromuscular junction development / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / 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 / 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 / cell surface receptor protein tyrosine kinase signaling pathway / GRB2 events in ERBB2 signaling / myelination / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / Downregulation of ERBB2:ERBB3 signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / phosphatidylinositol 3-kinase/protein kinase B signal transduction / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / positive regulation of epithelial cell proliferation / positive regulation of translation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / neuromuscular junction / 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 / transmembrane signaling receptor activity / Constitutive Signaling by Aberrant PI3K in Cancer / 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 / cell surface receptor signaling pathway / early endosome / receptor complex / endosome membrane / intracellular signal transduction / positive regulation of protein phosphorylation / apical plasma membrane / 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 / identical protein binding / membrane / nucleus / plasma membrane
Similarity search - Function
: / 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 ...: / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-03Q / Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsSkene, R.J. / Aertgeerts, K. / Sogabe, S.
CitationJournal: J.Biol.Chem. / Year: 2011
Title: Structural Analysis of the Mechanism of Inhibition and Allosteric Activation of the Kinase Domain of HER2 Protein.
Authors: Aertgeerts, K. / Skene, R. / Yano, J. / Sang, B.C. / Zou, H. / Snell, G. / Jennings, A. / Iwamoto, K. / Habuka, N. / Hirokawa, A. / Ishikawa, T. / Tanaka, T. / Miki, H. / Ohta, Y. / Sogabe, S.
History
DepositionNov 23, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Sep 6, 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 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase erbB-2
B: Receptor tyrosine-protein kinase erbB-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,4464
Polymers76,4582
Non-polymers9882
Water3,423190
1
A: Receptor tyrosine-protein kinase erbB-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7232
Polymers38,2291
Non-polymers4941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Receptor tyrosine-protein kinase erbB-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7232
Polymers38,2291
Non-polymers4941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.705, 78.951, 152.675
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: 38229.012 Da / Num. of mol.: 2 / Fragment: kinase domain, residues 706-1009 / Mutation: M706A, Q711L, M712L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB2, HER2, MLN19, NEU, NGL / Plasmid: pFastBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04626, receptor protein-tyrosine kinase
#2: Chemical ChemComp-03Q / 2-{2-[4-({5-chloro-6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol


Mass: 493.866 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H19ClF3N5O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / 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: 1.92 Å3/Da / Density % sol: 35.92 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 20% PEG 3550, 200mM di-Ammonium Tartrate, 100 mM PIPES, pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 28, 2005
RadiationMonochromator: Si (220) Single mono / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 28773 / % possible obs: 99.5 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 15.1
Reflection shellResolution: 2.25→2.33 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.553 / Mean I/σ(I) obs: 1.82 / % possible all: 96.6

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Processing

Software
NameVersionClassification
Blu-Icedata collection
MOLREPphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1M14

1m14


Resolution: 2.25→50 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.92 / SU B: 17.529 / SU ML: 0.193 / Cross valid method: THROUGHOUT / ESU R Free: 0.255 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26035 1438 5.1 %RANDOM
Rwork0.18484 ---
obs0.18865 27014 99.16 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.366 Å2
Baniso -1Baniso -2Baniso -3
1-3.38 Å20 Å20 Å2
2---0.5 Å20 Å2
3----2.88 Å2
Refinement stepCycle: LAST / Resolution: 2.25→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4657 0 68 190 4915
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224837
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.271.9926553
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9495579
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.17822.981208
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.6115869
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0911545
X-RAY DIFFRACTIONr_chiral_restr0.0870.2728
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213598
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.01222907
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.3634726
X-RAY DIFFRACTIONr_scbond_it5.46741930
X-RAY DIFFRACTIONr_scangle_it7.86261826
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.252→2.31 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.371 104 -
Rwork0.266 1893 -
obs--95.78 %
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)
10.8172-0.3151-0.75491.10470.20953.24720.0255-0.0362-0.0746-0.15360.03040.028-0.0897-0.0576-0.05590.04920-0.0220.0129-0.00170.044512.479921.62534.0645
21.02690.0926-0.31310.7641-0.39152.59670.04460.01780.0333-0.03180.0039-0.03540.08810.0031-0.04850.03880.00260.00690.0181-0.03120.062430.100840.4937-4.086
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A706 - 1009
2X-RAY DIFFRACTION1A1
3X-RAY DIFFRACTION2B706 - 1009
4X-RAY DIFFRACTION2B2

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