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

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Basic information

Entry
Database: PDB / ID: 2aob
TitleCrystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain
ComponentsGrowth factor receptor-bound protein 2
KeywordsTRANSFERASE / Grb2 SH2 / peptide mimetic / domain swapping / Kinase signalling
Function / homology
Function and homology information


guanyl-nucleotide exchange factor adaptor activity / Grb2-EGFR complex / branching involved in labyrinthine layer morphogenesis / STAT5 Activation / Co-inhibition by BTLA / neurotrophin TRKA receptor binding / COP9 signalosome / 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 / Co-inhibition by BTLA / neurotrophin TRKA receptor binding / COP9 signalosome / Activated NTRK2 signals through PI3K / MET receptor recycling / transmembrane receptor protein tyrosine kinase adaptor activity / Signaling by cytosolic FGFR1 fusion mutants / Interleukin-15 signaling / negative regulation of natural killer cell mediated cytotoxicity / MET activates PTPN11 / MET activates RAP1 and RAC1 / vesicle membrane / Signaling by LTK / CD28 dependent Vav1 pathway / MET activates PI3K/AKT signaling / Signal regulatory protein family interactions / epidermal growth factor receptor binding / Regulation of KIT signaling / PI-3K cascade:FGFR3 / natural killer cell mediated cytotoxicity / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / endodermal cell differentiation / positive regulation of actin filament polymerization / GRB2:SOS provides linkage to MAPK signaling for Integrins / RHOU GTPase cycle / regulation of MAPK cascade / RET signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K events in ERBB2 signaling / PI3K Cascade / signal transduction in response to DNA damage / SOS-mediated signalling / fibroblast growth factor receptor signaling pathway / Activated NTRK3 signals through RAS / Role of LAT2/NTAL/LAB on calcium mobilization / Activated NTRK2 signals through RAS / Interleukin receptor SHC signaling / SHC1 events in ERBB4 signaling / RHO GTPases Activate WASPs and WAVEs / Signal attenuation / Signalling to RAS / GAB1 signalosome / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Schwann cell development / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / ephrin receptor binding / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / 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 / phosphotyrosine residue binding / myelination / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / FCERI mediated Ca+2 mobilization / GRB2 events in ERBB2 signaling / Downstream signal transduction / insulin-like growth factor receptor signaling pathway / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / T cell activation / InlB-mediated entry of Listeria monocytogenes into host cell / cellular response to ionizing radiation / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / Regulation of signaling by CBL / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling
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 / MIR / Resolution: 1.8 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: Advisory / 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 / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)55,35916
Polymers46,3014
Non-polymers9,05812
Water6,720373
1
A: Growth factor receptor-bound protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,3496
Polymers11,5751
Non-polymers3,7745
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)12,3302
Polymers11,5751
Non-polymers7551
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Growth factor receptor-bound protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,5945
Polymers11,5751
Non-polymers3,0194
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: 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
5
C: Growth factor receptor-bound protein 2
D: Growth factor receptor-bound protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6798
Polymers23,1502
Non-polymers4,5296
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8710 Å2
ΔGint-22 kcal/mol
Surface area11060 Å2
MethodPISA, PQS
6
A: Growth factor receptor-bound protein 2
B: Growth factor receptor-bound protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6798
Polymers23,1502
Non-polymers4,5296
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8670 Å2
ΔGint-19 kcal/mol
Surface area11040 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)87.817, 106.191, 102.083
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 11575.156 Da / Num. of mol.: 4 / 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.: 12 / Source method: obtained synthetically / Formula: C41H46N4O10
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 373 / 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: 2.5 Å3/Da / Density % sol: 50 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 5.7
Details: PEG 3350, sodium acetate, sodium chloride, pH 5.7, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
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: 1.78→25 Å / Num. all: 45886 / Num. obs: 44270 / % possible obs: 96 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 7.3 % / Biso Wilson estimate: 28.9 Å2 / Net I/σ(I): 27
Reflection shellResolution: 1.78→1.84 Å / % possible all: 87.5

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
MAR345data collection
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MIR / Resolution: 1.8→25 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.919 / SU B: 6.69 / SU ML: 0.133 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.168 / ESU R Free: 0.167 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29342 2245 5.1 %RANDOM
Rwork0.23212 ---
obs0.2352 42084 99.68 %-
all-45886 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.014 Å2
Baniso -1Baniso -2Baniso -3
1--0.2 Å20 Å20 Å2
2--0.35 Å20 Å2
3----0.15 Å2
Refinement stepCycle: LAST / Resolution: 1.8→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3003 0 660 373 4036
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0213792
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg3.0312.1225158
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0985374
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.4922.739157
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.65215482
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7331524
X-RAY DIFFRACTIONr_chiral_restr0.6470.2505
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.023024
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2320.21660
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3240.22594
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2370.2336
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2040.270
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.260.212
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4251.52002
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.28123075
X-RAY DIFFRACTIONr_scbond_it3.09432152
X-RAY DIFFRACTIONr_scangle_it4.3774.52083
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.333 169 -
Rwork0.303 3055 -
obs--99.85 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.2742-0.00950.67140.1385-0.1522.5735-0.0149-0.02740.0373-0.01070.0106-0.0050.2623-0.05230.0043-0.1323-0.0026-0.0074-0.13730.0037-0.071821.564527.92950.2294
21.3785-0.11892.34070.0103-0.20193.9744-0.2095-0.04660.19770.01750.2683-0.04420.204-0.0038-0.0587-0.09260.0057-0.0533-0.0392-0.0023-0.094721.779427.6330.0624
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA56 - 1202 - 66
2X-RAY DIFFRACTION1BB59 - 1205 - 66
3X-RAY DIFFRACTION1CC56 - 1202 - 66
4X-RAY DIFFRACTION1DD59 - 1205 - 66
5X-RAY DIFFRACTION2AA121 - 15167 - 97
6X-RAY DIFFRACTION2BB121 - 15167 - 97
7X-RAY DIFFRACTION2CC121 - 15167 - 97
8X-RAY DIFFRACTION2DD121 - 15167 - 97

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