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- PDB-8vb5: Crystal structure of kinase domain of HER2 Exon 20 insertion muta... -

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Basic information

Entry
Database: PDB / ID: 8vb5
TitleCrystal structure of kinase domain of HER2 Exon 20 insertion mutant in complex with tucatinib
ComponentsReceptor tyrosine-protein kinase erbB-2
KeywordsTRANSFERASE / Receptor tyrosine kinase / YVMA insertion / alpha-C helix / A-loop
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 / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / neuromuscular junction development / ERBB2 Activates PTK6 Signaling / enzyme-linked receptor protein signaling pathway / positive regulation of Rho protein signal transduction / ERBB2-ERBB3 signaling pathway / 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 / 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 / Schwann cell development / regulation of ERK1 and ERK2 cascade / coreceptor activity / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / positive regulation of MAP kinase activity / GRB2 events in ERBB2 signaling / positive regulation of cell adhesion / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / Downregulation of ERBB2:ERBB3 signaling / Constitutive Signaling by Overexpressed ERBB2 / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of epithelial cell proliferation / basal plasma membrane / positive regulation of translation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / Signaling by ERBB2 TMD/JMD mutants / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / neuromuscular junction / cellular response to growth factor stimulus / peptidyl-tyrosine phosphorylation / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / epidermal growth factor receptor signaling pathway / ruffle membrane / Downregulation of ERBB2 signaling / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / presynaptic membrane / heart development / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protein tyrosine kinase activity / basolateral plasma membrane / early endosome / cell population proliferation / receptor complex / cell surface receptor signaling pathway / positive regulation of MAPK cascade
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
: / DI(HYDROXYETHYL)ETHER / Receptor tyrosine-protein kinase erbB-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.48 Å
AuthorsRana, N. / Campbell, J. / Dou, Y.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: To Be Published
Title: Crystal structure of kinase domain of HER2 Exon 20 insertion mutant in complex with tucatinib
Authors: Rana, N. / Campbell, J. / Dou, Y.
History
DepositionDec 12, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)39,68810
Polymers38,6941
Non-polymers9959
Water4,396244
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)34.412, 81.699, 94.936
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#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: 38693.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB2, HER2, MLN19, NEU, NGL / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P04626, receptor protein-tyrosine kinase

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Non-polymers , 5 types, 253 molecules

#2: Chemical ChemComp-A1AAC / Tucatinib / N~6~-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-N~4~-(3-methyl-4-{[(4R)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]oxy}phenyl)quinazoline-4,6-diamine / Tukysa / ONT-380 / ARRY-380


Mass: 480.521 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H24N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C4H10O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 1.72 Å3/Da / Density % sol: 28.67 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Bicine pH 8.5, 11% w/v PEG 1500, 0.5mM Tucatinib

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Data collection

DiffractionMean temperature: 298 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.979145 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Oct 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979145 Å / Relative weight: 1
ReflectionResolution: 1.48→61.93 Å / Num. obs: 43125 / % possible obs: 99.73 % / Redundancy: 6.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.044 / Rpim(I) all: 0.028 / Rrim(I) all: 0.052 / Net I/σ(I): 18.7
Reflection shellResolution: 1.48→1.518 Å / Num. unique obs: 3076 / CC1/2: 0.999

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
autoPROCv1.0.5data reduction
Aimlessv0.7.7data scaling
PHASERv2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.48→61.93 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.964 / SU B: 2.454 / SU ML: 0.042 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.084 / ESU R Free: 0.071 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.187 2294 5.1 %RANDOM
Rwork0.1447 ---
obs0.1469 43125 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 70.86 Å2 / Biso mean: 23.21 Å2 / Biso min: 12.04 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20 Å20 Å2
2--0.26 Å2-0 Å2
3----0.52 Å2
Refinement stepCycle: final / Resolution: 1.48→61.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2306 0 68 244 2618
Biso mean--27.04 34.91 -
Num. residues----289
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0132542
X-RAY DIFFRACTIONr_bond_other_d0.0010.0152494
X-RAY DIFFRACTIONr_angle_refined_deg1.2971.673450
X-RAY DIFFRACTIONr_angle_other_deg1.3041.5915738
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2695316
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.49920.313128
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.69615452
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7441524
X-RAY DIFFRACTIONr_chiral_restr0.070.2317
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022875
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02592
X-RAY DIFFRACTIONr_mcbond_it1.3892.151228
X-RAY DIFFRACTIONr_mcbond_other1.3712.1471227
X-RAY DIFFRACTIONr_mcangle_it1.7843.2311556
X-RAY DIFFRACTIONr_rigid_bond_restr0.84435036
LS refinement shellResolution: 1.48→1.518 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.231 152 -
Rwork0.183 3076 -
all-3228 -
obs--97.91 %

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