[English] 日本語
Yorodumi
- PDB-8u8x: crystal structure of the receptor tyrosine kinase Human HER2 (ERB... -

+
Open data


ID or keywords:

Loading...

-
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 / 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 / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2 Activates PTK6 Signaling / enzyme-linked receptor protein signaling pathway / neuromuscular junction development / ERBB2-ERBB3 signaling pathway / 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 / positive regulation of transcription by RNA polymerase I / positive regulation of MAP kinase activity / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / oligodendrocyte differentiation / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / Schwann cell development / Downregulation of ERBB2:ERBB3 signaling / coreceptor activity / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / transmembrane receptor protein tyrosine kinase activity / GRB2 events in ERBB2 signaling / positive regulation of cell adhesion / SHC1 events in ERBB2 signaling / basal plasma membrane / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / cellular response to epidermal growth factor stimulus / peptidyl-tyrosine phosphorylation / positive regulation of translation / positive regulation of epithelial cell proliferation / neuromuscular junction / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / Signaling by ERBB2 TMD/JMD mutants / Downregulation of ERBB2 signaling / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / cellular response to growth factor stimulus / ruffle membrane / epidermal growth factor receptor signaling pathway / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / heart development / presynaptic membrane / 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 surface receptor signaling pathway / endosome membrane / cell population proliferation / protein phosphorylation / receptor complex / positive regulation of MAPK cascade / intracellular signal transduction / apical plasma membrane / protein heterodimerization activity / signaling receptor binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / signal transduction / nucleoplasm / ATP binding / identical protein binding / nucleus / membrane / plasma membrane / cytosol
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: 1.69 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
Revision 1.2Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more