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- PDB-2aoa: Crystal structures of a high-affinity macrocyclic peptide mimetic... -

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Basic information

Entry
Database: PDB / ID: 2aoa
TitleCrystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain
ComponentsGrowth factor receptor-bound protein 2GRB2
KeywordsTRANSFERASE / Grb2 SH2 / domain-swapped / peptide mimetic
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 / 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
Chem-S1S / Growth factor receptor-bound protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsPhan, J. / Shi, Z.D. / Burke, T.R. / Waugh, D.S.
CitationJournal: J.Mol.Biol. / Year: 2005
Title: Crystal Structures of a High-affinity Macrocyclic Peptide Mimetic in Complex with the Grb2 SH2 Domain.
Authors: Phan, J. / Shi, Z.D. / Burke, T.R. / Waugh, D.S.
History
DepositionAug 12, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 4, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Derived calculations / Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.4Feb 14, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,7416
Polymers23,1502
Non-polymers2,5914
Water1,856103
1
A: Growth factor receptor-bound protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,0853
Polymers11,5751
Non-polymers1,5102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Growth factor receptor-bound protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,6563
Polymers11,5751
Non-polymers1,0812
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6730 Å2
ΔGint-22 kcal/mol
Surface area10140 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)88.173, 102.659, 107.240
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number22
Space group name H-MF222

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Components

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


Mass: 11575.156 Da / Num. of mol.: 2 / Fragment: SH2 (residues 55 - 153)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRB2, ASH / Production host: Escherichia coli (E. coli) / References: UniProt: P62993
#2: Chemical ChemComp-S1S / 2-(4-((9S,10S,14S,Z)-18-(2-AMINO-2-OXOETHYL)-9-(CARBOXYMETHYL)-14-(NAPHTHALEN-1-YLMETHYL)-8,17,20-TRIOXO-7,16,19-TRIAZASPIRO[5.14]ICOS-11-EN-10-YL)PHENYL)MALONIC ACID


Mass: 754.825 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C41H46N4O10
#3: Chemical ChemComp-P33 / 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL / HEPTAETHYLENE GLYCOL / PEG330 / Polyethylene glycol


Mass: 326.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H30O8 / Comment: precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 103 / 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: 2.6 Å3/Da / Density % sol: 52.7 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 5.7
Details: PEG3350, sodium chloride, sodium acetate, pH 5.7, VAPOR DIFFUSION, temperature 298K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jun 20, 2004
RadiationMonochromator: Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.99→56.8 Å / Num. all: 15744 / Num. obs: 13733 / % possible obs: 95 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5 % / Biso Wilson estimate: 37.9 Å2 / Net I/σ(I): 17.9
Reflection shellResolution: 2→2.07 Å / % possible all: 91

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
MAR345data collection
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.99→56.8 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.896 / SU B: 5.823 / SU ML: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.22 / ESU R Free: 0.208 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30711 799 5.1 %RANDOM
Rwork0.24555 ---
obs0.24862 13733 94.02 %-
all-15744 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 40.738 Å2
Baniso -1Baniso -2Baniso -3
1--0.79 Å20 Å20 Å2
2---0.22 Å20 Å2
3---1.01 Å2
Refinement stepCycle: LAST / Resolution: 1.99→56.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1302 0 187 103 1592
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0440.0211534
X-RAY DIFFRACTIONr_bond_other_d0.0030.021343
X-RAY DIFFRACTIONr_angle_refined_deg3.7552.0552072
X-RAY DIFFRACTIONr_angle_other_deg1.83633107
X-RAY DIFFRACTIONr_dihedral_angle_1_deg10.2655167
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.6580.2211
X-RAY DIFFRACTIONr_gen_planes_refined0.0190.021705
X-RAY DIFFRACTIONr_gen_planes_other0.0130.02375
X-RAY DIFFRACTIONr_nbd_refined0.2680.2310
X-RAY DIFFRACTIONr_nbd_other0.2870.21581
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.1280.2950
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.3470.284
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0730.23
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2490.236
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4650.27
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.0711.5855
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.39721340
X-RAY DIFFRACTIONr_scbond_it4.6763679
X-RAY DIFFRACTIONr_scangle_it6.724.5732
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.995→2.047 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.317 27
Rwork0.285 693

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