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- PDB-2huw: X-ray crystal structure of the Grb2 SH2 domain complexed to a con... -

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Basic information

Entry
Database: PDB / ID: 2huw
TitleX-ray crystal structure of the Grb2 SH2 domain complexed to a constrained and cyclopropane-derived ligand
ComponentsGrowth factor receptor-bound protein 2GRB2
KeywordsHORMONE/GROWTH FACTOR / cylcopropane / contrained / Grb2 / SH2 / preorganization / HORMONE-GROWTH FACTOR 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 / vesicle membrane / 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 / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / vesicle membrane / 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 / epidermal growth factor receptor binding / Regulation of KIT signaling / 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 / SOS-mediated signalling / RET signaling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / SHC1 events in ERBB4 signaling / RHO GTPases Activate WASPs and WAVEs / Signalling to RAS / fibroblast growth factor receptor signaling pathway / signal transduction in response to DNA damage / 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 / 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 / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / myelination / 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 / FCERI mediated Ca+2 mobilization / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / 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 / FCERI mediated MAPK activation / Negative regulation of FGFR2 signaling / FCGR3A-mediated phagocytosis / Negative regulation of FGFR4 signaling / EGFR downregulation / Negative regulation of FGFR1 signaling / B cell receptor signaling pathway / Signaling by ERBB2 TMD/JMD mutants / Spry regulation of FGF 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
PHOSPHATE ION / Chem-YVN / Growth factor receptor-bound protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsBenfield, A.P. / Martin, S.F.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2006
Title: Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein-Ligand Interactions.
Authors: Benfield, A.P. / Teresk, M.G. / Plake, H.R. / Delorbe, J.E. / Millspaugh, L.E. / Martin, S.F.
History
DepositionJul 27, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 15, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
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_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_ref_seq_dif.details / _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)28,5255
Polymers27,3752
Non-polymers1,1503
Water2,720151
1
A: Growth factor receptor-bound protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,2152
Polymers13,6871
Non-polymers5271
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)14,3103
Polymers13,6871
Non-polymers6222
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)31.824, 85.490, 41.436
Angle α, β, γ (deg.)90.00, 92.60, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 13687.465 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 / Production host: Escherichia coli (E. coli) / References: UniProt: P62993
#2: Chemical ChemComp-YVN / N-({(1R,2R,3S)-2-(methylcarbamoyl)-3-[4-(phosphonooxy)phenyl]cyclopropyl}carbonyl)-L-valyl-L-aspartamide


Mass: 527.465 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N5O9P
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2.06 Å3/Da / Density % sol: 40.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: Ligand (cpYVN) was added to a 1.5 molar excess to a solution of 50 mg/ml Grb2-SH2 in 50 mM sodium cacodylate at PH 6.0. This solution was mixed with an equal volume of 4% (v/v) PEG 400, 2.0 ...Details: Ligand (cpYVN) was added to a 1.5 molar excess to a solution of 50 mg/ml Grb2-SH2 in 50 mM sodium cacodylate at PH 6.0. This solution was mixed with an equal volume of 4% (v/v) PEG 400, 2.0 M (NH4)2PO4., VAPOR DIFFUSION, HANGING DROP, temperature 293K

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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: Jan 1, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→20 Å / Num. all: 16559 / Num. obs: 16569 / % possible obs: 94.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Rmerge(I) obs: 0.06 / Χ2: 1.198 / Net I/σ(I): 24.4
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
1.9-1.970.2716651.33895.5
1.97-2.050.17216761.41397.7
2.05-2.140.1417161.00997.4
2.14-2.250.10716811.35697
2.25-2.390.08516681.33896.6
2.39-2.580.07516781.20195.2
2.58-2.840.06116721.01194.6
2.84-3.250.0516321.17993.7
3.25-4.080.04916150.99292.2
4.08-200.04815661.20487.7

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT2data extraction
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→20 Å / FOM work R set: 0.857 / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.227 833 4.8 %Random
Rwork0.195 ---
all0.195 16538 --
obs0.227 16538 94.8 %-
Solvent computationBsol: 62.591 Å2
Displacement parametersBiso mean: 25.096 Å2
Baniso -1Baniso -2Baniso -3
1-1.224 Å20 Å2-0.688 Å2
2--2.847 Å20 Å2
3----4.07 Å2
Refinement stepCycle: LAST / Resolution: 1.9→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1642 0 77 151 1870
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.386
X-RAY DIFFRACTIONc_mcbond_it1.461.5
X-RAY DIFFRACTIONc_scbond_it1.9632
X-RAY DIFFRACTIONc_mcangle_it2.3192
X-RAY DIFFRACTIONc_scangle_it2.9452.5
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 16

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs
1.9-1.940.419510.3099621013
1.94-1.990.276540.23410361090
1.99-2.040.223560.2069781034
2.04-2.090.269540.20610171071
2.09-2.150.261500.20410061056
2.15-2.220.227550.19710011056
2.22-2.30.265560.2069951051
2.3-2.390.218480.1859901038
2.39-2.50.277530.2069811034
2.5-2.630.269480.210101058
2.63-2.80.273640.219501014
2.8-3.010.236480.1949771025
3.01-3.320.199480.1779741022
3.32-3.790.188550.1749621017
3.79-4.770.169500.165944994
4.77-200.192430.207922965
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1CNS_TOPPAR:protein_rep.paramCNS_TOPPAR:protein.top
X-RAY DIFFRACTION2cpYVN.paramcpYVN.top
X-RAY DIFFRACTION3CNS_TOPPAR:water_rep.paramCNS_TOPPAR:water.top
X-RAY DIFFRACTION4CNS_TOPPAR:ion.paramCNS_TOPPAR:ion.top

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