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- PDB-8vqd: HER2 S310F in complex with TL1 Fab -

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Basic information

Entry
Database: PDB / ID: 8vqd
TitleHER2 S310F in complex with TL1 Fab
Components
  • Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion
  • Variable Heavy chain of TL1 Fab
  • Variable Light chain of TL1 Fab
KeywordsSIGNALING PROTEIN / HER2 / Fab / Tyrosine kinase 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 / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / 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 / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / positive regulation of Rho protein signal transduction / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / neuromuscular junction development / 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 / ERBB2-ERBB3 signaling pathway / enzyme-linked receptor protein signaling pathway / positive regulation of transcription by RNA polymerase I / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / regulation of angiogenesis / coreceptor activity / Schwann cell development / Signaling by ERBB2 / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to epidermal growth factor stimulus / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / transmembrane receptor protein tyrosine kinase activity / GRB2 events in ERBB2 signaling / phosphatidylinositol 3-kinase/protein kinase B signal transduction / SHC1 events in ERBB2 signaling / positive regulation of cell adhesion / Downregulation of ERBB2:ERBB3 signaling / Constitutive Signaling by Overexpressed ERBB2 / 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 / wound healing / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / neuromuscular junction / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / neuron differentiation / 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 / heart development / presynaptic membrane / 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 / receptor complex / cell surface receptor signaling pathway / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsBang, I. / Koide, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain
Authors: Bang, I. / Hattori, T. / Leloup, N. / Corrado, A. / Koide, A. / Geles, K. / Buck, E. / Koide, S.
History
DepositionJan 18, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion
C: Variable Heavy chain of TL1 Fab
B: Variable Light chain of TL1 Fab
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,5394
Polymers150,1143
Non-polymers4241
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion / 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: 99261.641 Da / Num. of mol.: 1 / Mutation: S310F
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 Variable Heavy chain of TL1 Fab


Mass: 27512.574 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody Variable Light chain of TL1 Fab


Mass: 23339.900 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: HER2 S310F in complex with TL1 Fab / Type: COMPLEX
Details: Fab that only binds to HER2 S310F/Y but not to WT is in complex with HER2 S310F
Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 150 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Details: 20mM Tris, 150mM NaCl, 0.7mM fluorinated octyl maltoside
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMTrisC4H11NO31
30.7 mMFluorinated Octyl MalosideC20H25F13O111
SpecimenConc.: 1.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: This sample was was eluted as a monodisperse peak with gel filtration
Specimen supportDetails: The grid was coated with goldfoil prior and discharged with current at 15mA for 25s, held for 10s.
Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277.15 K
Details: Vitrification carried out with blot force 5, blot time 4 s

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 900 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 2 sec. / Electron dose: 57.43 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 8985
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategoryDetails
1Warp1.0.9particle selectionOn-fly picking
2Topaz0.2.5particle selectionRepicked selected particles using topaz
3Leginon3.6image acquisition
5cryoSPARC4.2.1CTF correctionPatchCTF
8UCSF ChimeraX1.6.1model fitting
9Coot0.9.8.1model fitting
11PHENIX1.20.1_4487model refinement
12Coot0.9.8.1model refinement
16cryoSPARC4.2.13D reconstructionLocal refinment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 161060 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building

3D fitting-ID: 1

IDPDB-IDPdb chain-IDAccession codeChain-IDChain residue rangeInitial refinement model-IDPdb chain residue rangeSource nameType
17MN6

7mn6

B7MN6B23-542123-542PDBexperimental model
2SwissModelin silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035817
ELECTRON MICROSCOPYf_angle_d0.6487903
ELECTRON MICROSCOPYf_dihedral_angle_d4.829807
ELECTRON MICROSCOPYf_chiral_restr0.046878
ELECTRON MICROSCOPYf_plane_restr0.0051025

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