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- PDB-3n8m: Crystal Structure of the Grb2 SH2 Domain in Complex with An Acycl... -

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Basic information

Entry
Database: PDB / ID: 3n8m
TitleCrystal Structure of the Grb2 SH2 Domain in Complex with An Acyclic Ligand Having the Sequence pYVNVP
Components
  • Growth factor receptor-bound protein 2
  • PEPTIDE
KeywordsPROTEIN BINDING/PEPTIDE / Grb2 SH2 domain / ligand preorganization / macrocycles / macrocyclic ligands / PROTEIN BINDING-PEPTIDE complex
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 / 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 ...guanyl-nucleotide exchange factor adaptor activity / Grb2-EGFR complex / branching involved in labyrinthine layer morphogenesis / STAT5 Activation / COP9 signalosome / 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 / vesicle membrane / Costimulation by the CD28 family / CD28 dependent Vav1 pathway / Signaling by LTK / MET activates PI3K/AKT signaling / Signal regulatory protein family interactions / natural killer cell mediated cytotoxicity / positive regulation of actin filament polymerization / epidermal growth factor receptor binding / Regulation of KIT signaling / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / STAT5 activation downstream of FLT3 ITD mutants / 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 / PI3K Cascade / RET signaling / SOS-mediated signalling / insulin receptor substrate binding / Activated NTRK3 signals through RAS / Interleukin-3, Interleukin-5 and GM-CSF signaling / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / fibroblast growth factor receptor signaling pathway / Signalling to RAS / signal transduction in response to DNA damage / RHO GTPases Activate WASPs and WAVEs / GAB1 signalosome / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / Signal attenuation / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Schwann cell development / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / FRS-mediated FGFR1 signaling / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / phosphotyrosine residue binding / Signaling by FGFR1 in disease / myelination / ephrin receptor binding / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / FCERI mediated Ca+2 mobilization / insulin-like growth factor receptor signaling pathway / T cell activation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / InlB-mediated entry of Listeria monocytogenes into host cell / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / cellular response to ionizing radiation / Negative regulation of FGFR2 signaling / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Negative regulation of FGFR3 signaling / B cell receptor signaling pathway / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation
Similarity search - Function
GRB2, N-terminal SH3 domain / GRB2, C-terminal SH3 domain / Grb2-like / SH2 domain / SHC Adaptor Protein / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain ...GRB2, N-terminal SH3 domain / GRB2, C-terminal SH3 domain / Grb2-like / SH2 domain / SHC Adaptor Protein / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Growth factor receptor-bound protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsWhiddon, B.B. / Clements, J.H. / Martin, S.F.
CitationJournal: ACS MED.CHEM.LETT. / Year: 2010
Title: Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions.
Authors: Delorbe, J.E. / Clements, J.H. / Whiddon, B.B. / Martin, S.F.
History
DepositionMay 28, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 15, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 22, 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

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Assembly

Deposited unit
A: Growth factor receptor-bound protein 2
B: PEPTIDE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6323
Polymers14,5402
Non-polymers921
Water1,928107
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area920 Å2
ΔGint-7 kcal/mol
Surface area6330 Å2
MethodPISA
2
A: Growth factor receptor-bound protein 2
B: PEPTIDE
hetero molecules

A: Growth factor receptor-bound protein 2
B: PEPTIDE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,2656
Polymers29,0814
Non-polymers1842
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_555-y,-x,-z+1/21
Buried area4160 Å2
ΔGint-30 kcal/mol
Surface area10340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.240, 49.240, 86.128
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

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


Mass: 13758.543 Da / Num. of mol.: 1 / Fragment: Grb2 SH2 domain, residues 55-153
Source method: isolated from a genetically manipulated source
Details: Protein was expressed with a C-terminal six-HIS tag
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 PEPTIDE


Mass: 781.832 Da / Num. of mol.: 1 / Source method: obtained synthetically
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 107 / Source method: isolated from a natural source / Formula: H2O

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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: 1.795 Å3/Da / Density % sol: 31.48 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: Ligand in lyophilized powder form was dissolved in a 7.2 mg/mL solution of Grb2 SH2 in water such to give a protein/ligand molar ratio of 1:1.7. 4 uL of this solution was mixed with 3 uL of ...Details: Ligand in lyophilized powder form was dissolved in a 7.2 mg/mL solution of Grb2 SH2 in water such to give a protein/ligand molar ratio of 1:1.7. 4 uL of this solution was mixed with 3 uL of 12% v/v glycerol, 1.5 M ammonium sulfate, 0.1 M TRIS, pH 8.5 to create the hanging drop, which yielded crystals of the protein-ligand complex after 8 weeks, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jul 27, 2007
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: 1.86→34.82 Å / Num. all: 9489 / Num. obs: 9451 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 22.1 % / Rmerge(I) obs: 0.066 / Net I/σ(I): 60.6
Reflection shellResolution: 1.86→1.93 Å / Redundancy: 19.5 % / Rmerge(I) obs: 0.152 / Mean I/σ(I) obs: 21.1 / Num. unique all: 912 / % possible all: 97

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Processing

Software
NameClassification
CrystalCleardata collection
MOLREPphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2HUW

2huw


Resolution: 2→34.82 Å / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2239 385 -random
Rwork0.1867 ---
all-7649 --
obs-7636 99.8 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.52 Å20 Å20 Å2
2---0.52 Å20 Å2
3---1.04 Å2
Refinement stepCycle: LAST / Resolution: 2→34.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms872 0 6 107 985

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