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- PDB-3n84: Crystal Structure of the Grb2 SH2 Domain in Complex with a 23-Mem... -

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Basic information

Entry
Database: PDB / ID: 3n84
TitleCrystal Structure of the Grb2 SH2 Domain in Complex with a 23-Membered Macrocyclic Ligand Having the Sequence pYVNVP
Components
  • 23-membered peptide-like macrocyclic ligand
  • Growth factor receptor-bound protein 2GRB2
Keywordsprotein binding/peptide / ligand preorganization / macrocycles / macrocyclic ligands / Golgi apparatus / Host-virus interaction / Phosphoprotein / 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 / 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
Growth factor receptor-bound protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsClements, 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 27, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2011Provider: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.ptnr2_label_atom_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
E: Growth factor receptor-bound protein 2
F: Growth factor receptor-bound protein 2
G: 23-membered peptide-like macrocyclic ligand
H: 23-membered peptide-like macrocyclic ligand
I: 23-membered peptide-like macrocyclic ligand
J: 23-membered peptide-like macrocyclic ligand
K: 23-membered peptide-like macrocyclic ligand
L: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,89222
Polymers83,15212
Non-polymers74010
Water13,115728
1
A: Growth factor receptor-bound protein 2
E: Growth factor receptor-bound protein 2
G: 23-membered peptide-like macrocyclic ligand
K: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,9728
Polymers27,7174
Non-polymers2554
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5250 Å2
ΔGint-60 kcal/mol
Surface area11200 Å2
MethodPISA
2
A: Growth factor receptor-bound protein 2
G: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,9304
Polymers13,8592
Non-polymers712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-28 kcal/mol
Surface area6960 Å2
MethodPISA
3
B: Growth factor receptor-bound protein 2
D: Growth factor receptor-bound protein 2
H: 23-membered peptide-like macrocyclic ligand
J: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,9026
Polymers27,7174
Non-polymers1842
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4460 Å2
ΔGint-36 kcal/mol
Surface area11000 Å2
MethodPISA
4
B: Growth factor receptor-bound protein 2
H: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,9513
Polymers13,8592
Non-polymers921
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area970 Å2
ΔGint-9 kcal/mol
Surface area6990 Å2
MethodPISA
5
F: Growth factor receptor-bound protein 2
L: 23-membered peptide-like macrocyclic ligand
hetero molecules

C: Growth factor receptor-bound protein 2
I: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0188
Polymers27,7174
Non-polymers3014
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_455x-1,y,z1
Buried area5080 Å2
ΔGint-48 kcal/mol
Surface area11040 Å2
MethodPISA
6
C: Growth factor receptor-bound protein 2
I: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,8833
Polymers13,8592
Non-polymers241
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area940 Å2
ΔGint-16 kcal/mol
Surface area7000 Å2
MethodPISA
7
D: Growth factor receptor-bound protein 2
J: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,9513
Polymers13,8592
Non-polymers921
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area830 Å2
ΔGint-8 kcal/mol
Surface area6670 Å2
MethodPISA
8
E: Growth factor receptor-bound protein 2
K: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0434
Polymers13,8592
Non-polymers1842
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1530 Å2
ΔGint-14 kcal/mol
Surface area6860 Å2
MethodPISA
9
F: Growth factor receptor-bound protein 2
L: 23-membered peptide-like macrocyclic ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,1355
Polymers13,8592
Non-polymers2763
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1530 Å2
ΔGint-13 kcal/mol
Surface area6660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.223, 141.320, 62.452
Angle α, β, γ (deg.)90.00, 89.99, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-464-

HOH

21E-362-

HOH

31F-601-

HOH

DetailsThere are six biological units in the asymmetric unit (chains A-F) each present as a complex with the macrocyclic ligand (chains G-L)

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Components

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Protein / Protein/peptide , 2 types, 12 molecules ABCDEFGHIJKL

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


Mass: 13060.855 Da / Num. of mol.: 6 / Fragment: SH2 domain
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
23-membered peptide-like macrocyclic ligand


Mass: 797.832 Da / Num. of mol.: 6 / Source method: obtained synthetically / Details: pYVNVP-containing sequence

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Non-polymers , 4 types, 738 molecules

#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 728 / 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: 2.22 Å3/Da / Density % sol: 44.62 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: Ligand in lyoophilized powder form was dissolved in a 8.0 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 lyoophilized powder form was dissolved in a 8.0 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 30% w/v polyethylene glycol MW 4000, 0.2 M magnesium chloride hexahydrate, 0.1 M TRIS, pH 8.5 to create the hanging drop, which yielded usable crystals 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 11, 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: 1.69→50 Å / Num. all: 80867 / Num. obs: 73832 / % possible obs: 91.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.8 % / Rmerge(I) obs: 0.066 / Net I/σ(I): 24.5
Reflection shellResolution: 1.69→1.75 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.275 / Mean I/σ(I) obs: 3.7 / Num. unique all: 7850 / % possible all: 69.4

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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→50 Å / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2233 2376 -random
Rwork0.1803 ---
all-48588 --
obs-45980 94.6 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-2.396 Å20 Å20 Å2
2--0.138 Å20 Å2
3----2.535 Å2
Refinement stepCycle: LAST / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5505 0 45 728 6278

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