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- PDB-6wo2: Crystal Structure of the Grb2 SH2 Domain in Complex with a Tripep... -

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Basic information

Entry
Database: PDB / ID: 6wo2
TitleCrystal Structure of the Grb2 SH2 Domain in Complex with a Tripeptide: Ac-pY-Ac6c-N-isohexyl
Components
  • ACE-PTR-02K-ASN-U67
  • Growth factor receptor-bound protein 2GRB2
KeywordsPEPTIDE BINDING PROTEIN / Grb2 SH2 Ligand preorganization
Function / homology
Function and homology information


guanyl-nucleotide exchange factor adaptor activity / Grb2-EGFR complex / branching involved in labyrinthine layer morphogenesis / STAT5 Activation / COP9 signalosome / vesicle membrane / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / MET receptor recycling / transmembrane receptor protein tyrosine kinase adaptor activity ...guanyl-nucleotide exchange factor adaptor activity / Grb2-EGFR complex / branching involved in labyrinthine layer morphogenesis / STAT5 Activation / COP9 signalosome / vesicle membrane / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / MET receptor recycling / transmembrane receptor protein tyrosine kinase adaptor activity / Signaling by cytosolic FGFR1 fusion mutants / Interleukin-15 signaling / MET activates PTPN11 / MET activates RAP1 and RAC1 / CD28 dependent Vav1 pathway / Costimulation by the CD28 family / MET activates PI3K/AKT signaling / Signal regulatory protein family interactions / Regulation of KIT signaling / epidermal growth factor receptor binding / positive regulation of actin filament polymerization / PI-3K cascade:FGFR3 / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / endodermal cell differentiation / regulation of MAPK cascade / GRB2:SOS provides linkage to MAPK signaling for Integrins / RHOU GTPase cycle / PI3K events in ERBB2 signaling / Signaling by ALK fusions and activated point mutants / SOS-mediated signalling / Activated NTRK3 signals through RAS / RET signaling / Activated NTRK2 signals through RAS / insulin receptor substrate binding / PI3K Cascade / Interleukin-3, Interleukin-5 and GM-CSF signaling / SHC1 events in ERBB4 signaling / RHO GTPases Activate WASPs and WAVEs / Signalling to RAS / fibroblast growth factor receptor signaling pathway / GAB1 signalosome / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Signal attenuation / Interleukin receptor SHC signaling / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / signal transduction in response to DNA damage / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / myelination / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / phosphotyrosine residue binding / ephrin receptor binding / SHC1 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / InlB-mediated entry of Listeria monocytogenes into host cell / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / cellular response to ionizing radiation / Regulation of signaling by CBL / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR4 signaling / EGFR downregulation / Negative regulation of FGFR1 signaling / Signaling by ERBB2 TMD/JMD mutants / B cell receptor signaling pathway
Similarity search - Function
GRB2, N-terminal SH3 domain / GRB2, C-terminal SH3 domain / Grb2-like / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily ...GRB2, N-terminal SH3 domain / GRB2, C-terminal SH3 domain / Grb2-like / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain
Similarity search - Domain/homology
ISOPROPYL ALCOHOL / Growth factor receptor-bound protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsMartin, S.F. / Clements, J.H.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)GM 84965 United States
National Science Foundation (NSF, United States)CHE 0750329 United States
Robert A. Welch FoundationF-0652 United States
Welch FoundationH-F-0032 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2020
Title: Some thermodynamic effects of varying nonpolar surfaces in protein-ligand interactions.
Authors: Cramer, D.L. / Cheng, B. / Tian, J. / Clements, J.H. / Wypych, R.M. / Martin, S.F.
History
DepositionApr 24, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2020Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Growth factor receptor-bound protein 2
B: Growth factor receptor-bound protein 2
C: ACE-PTR-02K-ASN-U67
D: ACE-PTR-02K-ASN-U67
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,9208
Polymers28,7364
Non-polymers1834
Water1,33374
1
A: Growth factor receptor-bound protein 2
C: ACE-PTR-02K-ASN-U67
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4684
Polymers14,3682
Non-polymers1002
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Growth factor receptor-bound protein 2
D: ACE-PTR-02K-ASN-U67
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4514
Polymers14,3682
Non-polymers832
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)32.225, 62.720, 90.137
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 / Protein/peptide , 2 types, 4 molecules ABCD

#1: Protein Growth factor receptor-bound protein 2 / GRB2 / Adapter protein GRB2 / Protein Ash / SH2/SH3 adapter GRB2


Mass: 13758.543 Da / Num. of mol.: 2 / Fragment: SH2 Domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRB2, ASH / Plasmid: PQE-60 / Production host: Escherichia coli (E. coli) / Strain (production host): SG13009 / References: UniProt: P62993
#2: Protein/peptide ACE-PTR-02K-ASN-U67


Mass: 609.652 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 78 molecules

#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL / Isopropyl alcohol


Mass: 60.095 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O

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Details

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

Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: An aqueous solution containing a 1.5 molar ratio of ligand to protein, ca. 10 mg/mL, was prepared. 4.0 ul of this solution was mixed with 3.0 ul of a precipitant solution containing 0.2 M ...Details: An aqueous solution containing a 1.5 molar ratio of ligand to protein, ca. 10 mg/mL, was prepared. 4.0 ul of this solution was mixed with 3.0 ul of a precipitant solution containing 0.2 M sodium citrate tribasic dihydrate, 0.1 M HEPES, and 20% v/v 2-propanol (Hampton crystal screen I, condition no. 27), and allowed to equilibrate with 350 ul of the aforementioned precipitant well solution. Usable crystals grew after 4 weeks

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 30, 2011
RadiationMonochromator: Blue max-flux confocal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.78→51.48 Å / Num. obs: 17182 / % possible obs: 94.6 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.072 / Χ2: 1.247 / Net I/σ(I): 14.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.78-1.843.20.54414141.224179.9
1.84-1.924.70.53616571.216193.1
1.92-25.80.3916821.279194.1
2-2.116.10.27516761.297194.7
2.11-2.246.10.21417121.279195.5
2.24-2.426.10.17217261.331196.1
2.42-2.666.10.11717761.223197.1
2.66-3.046.10.0817591.229197.4
3.04-3.8360.05218281.19198.4
3.83-51.485.60.04219521.189198.7

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.5.0109refinement
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4P9V

4p9v


Resolution: 2→51.48 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.886 / SU B: 5.243 / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.265 / ESU R Free: 0.224
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2754 645 5.2 %RANDOM
Rwork0.2001 ---
obs0.2039 11844 96.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 74 Å2 / Biso mean: 29.501 Å2 / Biso min: 8.53 Å2
Baniso -1Baniso -2Baniso -3
1-2.65 Å20 Å20 Å2
2---1.47 Å20 Å2
3----1.18 Å2
Refinement stepCycle: final / Resolution: 2→51.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1668 0 96 74 1838
Biso mean--33.95 30.29 -
Num. residues----202
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0221809
X-RAY DIFFRACTIONr_angle_refined_deg1.8871.9732417
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8685204
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.21323.22290
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.63815302
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9481514
X-RAY DIFFRACTIONr_chiral_restr0.1240.2242
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211377
LS refinement shellResolution: 2→2.052 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 50 -
Rwork0.214 822 -
all-872 -
obs--93.97 %

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