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- PDB-8u8x: crystal structure of the receptor tyrosine kinase Human HER2 (ERB... -

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Basic information

Entry
Database: PDB / ID: 8u8x
Titlecrystal structure of the receptor tyrosine kinase Human HER2 (ERBB2) YVMA mutant kinase domain in complex with inhibitor compound 27
ComponentsReceptor tyrosine-protein kinase erbB-2
KeywordsSIGNALING PROTEIN / TRANSFERASE/INHIBITOR / PROTO-ONCOGENE C-ERBB-2 / TYROSINE KINASE-TYPE CELL SURFACE / 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 / 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: 1.69 Å
AuthorsWang, J. / Mou, T.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Potent and Selective Covalent Inhibitors of HER2 WT and HER2 YVMA .
Authors: Hicken, E.J. / Brown, K. / Dwulet, N.C. / Gaudino, J.J. / Hansen, E.P. / Hartley, D.P. / Kowalski, J.P. / Laird, E.R. / Lazzara, N.C. / Li, B. / Mou, T.C. / Mutryn, M.F. / Oko, L. / Pajk, S. ...Authors: Hicken, E.J. / Brown, K. / Dwulet, N.C. / Gaudino, J.J. / Hansen, E.P. / Hartley, D.P. / Kowalski, J.P. / Laird, E.R. / Lazzara, N.C. / Li, B. / Mou, T.C. / Mutryn, M.F. / Oko, L. / Pajk, S. / Pipal, R.W. / Rosen, R.Z. / Shelp, R. / Singh, A. / Wang, J. / Wise, C.E. / Wong, C. / Wong, J.Y.
History
DepositionSep 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID

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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)40,2014
Polymers39,5241
Non-polymers6773
Water4,702261
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.420, 59.420, 82.484
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31
Space group name HallP31
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3

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Components

#1: Protein Receptor tyrosine-protein kinase erbB-2


Mass: 39523.551 Da / Num. of mol.: 1 / Fragment: kinase domain / Mutation: YVMA inserted after residue 84
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P04626
#2: Chemical ChemComp-W9N / 1-{(1R,3r,5S)-3-[(3M)-4-methyl-3-{3-methyl-4-[(1-methyl-1H-benzimidazol-5-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-8-azabicyclo[3.2.1]octan-8-yl}propan-1-one


Mass: 535.639 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H33N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.13 Å3/Da / Density % sol: 42.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 8% PEG 3350, 0.1M Tris pH8.5, 0.5M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Sep 26, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.69→29.71 Å / Num. obs: 36435 / % possible obs: 99.98 % / Redundancy: 9.4 % / Biso Wilson estimate: 22.36 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.091 / Rpim(I) all: 0.03261 / Rrim(I) all: 0.1008 / Net I/σ(I): 15.38
Reflection shellResolution: 1.69→1.75 Å / Rmerge(I) obs: 0.78 / Mean I/σ(I) obs: 8.3 / Num. unique obs: 3615 / CC1/2: 0.829 / Rpim(I) all: 0.2548 / Rrim(I) all: 0.7405

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
DENZOdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.69→29.71 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.99 / Phase error: 21.2094
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2025 1779 4.87 %
Rwork0.1645 34764 -
obs0.1661 36543 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.67 Å2
Refinement stepCycle: LAST / Resolution: 1.69→29.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2469 0 48 261 2778
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01032597
X-RAY DIFFRACTIONf_angle_d1.37593522
X-RAY DIFFRACTIONf_chiral_restr0.0788384
X-RAY DIFFRACTIONf_plane_restr0.0117449
X-RAY DIFFRACTIONf_dihedral_angle_d17.04521004
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.69-1.730.32931120.25712684X-RAY DIFFRACTION100
1.73-1.790.24041780.21422663X-RAY DIFFRACTION99.96
1.79-1.840.20251440.17582616X-RAY DIFFRACTION100
1.84-1.910.19721900.17772660X-RAY DIFFRACTION100
1.91-1.990.20761740.17842623X-RAY DIFFRACTION100
1.99-2.080.22951220.16412691X-RAY DIFFRACTION100
2.08-2.180.22631530.17542672X-RAY DIFFRACTION100
2.19-2.320.20981300.17982641X-RAY DIFFRACTION100
2.32-2.50.18671080.17062736X-RAY DIFFRACTION100
2.5-2.750.23631160.1692676X-RAY DIFFRACTION100
2.75-3.150.20471340.1782708X-RAY DIFFRACTION100
3.15-3.960.17231160.14432687X-RAY DIFFRACTION99.96
3.97-29.710.18341020.14352707X-RAY DIFFRACTION99.96

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