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- PDB-2l4k: Water refined solution structure of the human Grb7-SH2 domain in ... -

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Basic information

Entry
Database: PDB / ID: 2l4k
TitleWater refined solution structure of the human Grb7-SH2 domain in complex with the 10 amino acid peptide pY1139
Components
  • Growth factor receptor-bound protein 7
  • Receptor tyrosine-protein kinase erbB-2
KeywordsSIGNALING PROTEIN / Grb7 / SH2 domain / erbB2 receptor / water refinement
Function / homology
Function and homology information


negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / motor neuron axon guidance ...negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / regulation of microtubule-based process / ErbB-3 class receptor binding / motor neuron axon guidance / Sema4D induced cell migration and growth-cone collapse / RND1 GTPase cycle / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2 Activates PTK6 Signaling / enzyme-linked receptor protein signaling pathway / neuromuscular junction development / ERBB2-ERBB3 signaling pathway / positive regulation of Rho protein signal transduction / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / positive regulation of transcription by RNA polymerase I / positive regulation of MAP kinase activity / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / oligodendrocyte differentiation / RET signaling / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / Schwann cell development / Downregulation of ERBB2:ERBB3 signaling / coreceptor activity / Tie2 Signaling / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / transmembrane receptor protein tyrosine kinase activity / stress granule assembly / GRB2 events in ERBB2 signaling / phosphatidylinositol binding / Downstream signal transduction / positive regulation of cell adhesion / SHC1 events in ERBB2 signaling / basal plasma membrane / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / cellular response to epidermal growth factor stimulus / peptidyl-tyrosine phosphorylation / positive regulation of translation / positive regulation of epithelial cell proliferation / cell projection / neuromuscular junction / phosphatidylinositol 3-kinase/protein kinase B signal transduction / wound healing / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Downregulation of ERBB2 signaling / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / cellular response to growth factor stimulus / ruffle membrane / epidermal growth factor receptor signaling pathway / neuron differentiation / cytoplasmic stress granule / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / myelin sheath / heart development / presynaptic membrane / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protein tyrosine kinase activity / basolateral plasma membrane / early endosome / cell surface receptor signaling pathway / endosome membrane / cell population proliferation / protein phosphorylation / receptor complex / positive regulation of MAPK cascade / negative regulation of translation / intracellular signal transduction / positive regulation of cell migration / apical plasma membrane / protein heterodimerization activity
Similarity search - Function
Growth factor receptor-bound protein 7 / : / BPS (Between PH and SH2) domain / BPS (Between PH and SH2) / GRB/APBB1IP / APBB1IP, PH domain / RA like domain / Ras association (RalGDS/AF-6) domain / Ras-associating (RA) domain profile. / Ras-associating (RA) domain ...Growth factor receptor-bound protein 7 / : / BPS (Between PH and SH2) domain / BPS (Between PH and SH2) / GRB/APBB1IP / APBB1IP, PH domain / RA like domain / Ras association (RalGDS/AF-6) domain / Ras-associating (RA) domain profile. / Ras-associating (RA) domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / SH2 domain / SHC Adaptor Protein / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Growth factor receptor cysteine-rich domain superfamily / : / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ubiquitin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2 / Growth factor receptor-bound protein 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / molecular dynamics simulated annealing, simulated annealing
Model detailsbest PROCHECK statistics, model 3
AuthorsPias, S.C. / Ivancic, M. / Brescia, P.J. / Johnson, D.L. / Smith, D.E. / Daly, R.J. / Lyons, B.A.
Citation
Journal: Protein Pept.Lett. / Year: 2012
Title: Water-Refined Solution Structure of the Human Grb7-SH2 Domain in Complex with the erbB2 Receptor Peptide pY1139.
Authors: Pias, S.C. / Johnson, D.L. / Smith, D.E. / Lyons, B.A.
#1: Journal: J.Biomol.Nmr / Year: 2003
Title: Solution structure of the human Grb7-SH2 domain/erbB2 peptide complex and structural basis for Grb7 binding to ErbB2.
Authors: Ivancic, M. / Daly, R.J. / Lyons, B.A.
#2: Journal: J.Biomol.Nmr / Year: 2002
Title: Assignment of backbone 1H, 13C, and 15N resonances of human Grb7-SH2 domain in complex with a phosphorylated peptide ligand.
Authors: Brescia, P.J. / Ivancic, M. / Lyons, B.A.
#3: Journal: To Be Published
History
DepositionOct 7, 2010Deposition site: BMRB / Processing site: RCSB
Revision 1.0Nov 17, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 25, 2012Group: Database references
Revision 1.3Oct 3, 2012Group: Database references
Revision 1.4Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_nmr_software / 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 / _pdbx_nmr_software.name / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Growth factor receptor-bound protein 7
B: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)14,9572
Polymers14,9572
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 50structures with the lowest energy and the fewest restraint violations
RepresentativeModel #1best procheck statistics
DetailsTHE DIMERIC ANNOTATION IN REMARK 350 REFERS TO THE TWO CHAINS OF THE ASSEMBLY (PROTEIN DOMAIN AND LIGAND)

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Components

#1: Protein Growth factor receptor-bound protein 7 / GRB7 adapter protein / Epidermal growth factor receptor GRB-7 / B47


Mass: 13690.711 Da / Num. of mol.: 1 / Fragment: unp residues 415-532
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRB7 / Plasmid: pGEX-2T / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q14451
#2: Protein/peptide Receptor tyrosine-protein kinase erbB-2 / p185erbB2 / Tyrosine kinase-type cell surface receptor HER2 / Metastatic lymph node gene 19 protein / MLN 19


Mass: 1266.205 Da / Num. of mol.: 1 / Fragment: unp residues 1135-1144 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P04626, receptor protein-tyrosine kinase
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDType
1113D HNCA
1213D HN(CO)CA
1313D HN(CA)CB
1413D CBCA(CO)NH
1512D 15N HSQC
161CN NOESY-HSQC
1713D 15N NOESY-HSQC
1813D 13C NOESY-HSQC
1913D TOCSY-HSQC
11012D HMQC-J
11113D CBCANH
11213D (H)CCH-TOCSY
113113C, 15N→12C, 14N NOESY
114112C, 14N→13C, 15N NOESY
115112C, 14N→12C, 14N NOESY
116112C, 14N→12C, 14N TOCSY

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Sample preparation

DetailsContents: 0.6-0.8 mM [U-100% 13C; U-100% 15N] Grb7-SH2 domain-1, 0.6-0.8 mM [U-100% 13C; U-100% 15N] pY1139 peptide-2, 52.2 mM acetic acid-3, 100 mM sodium chloride-4, 5 mM DTT-5, 1 mM EDTA-6, 0.9 mM ...Contents: 0.6-0.8 mM [U-100% 13C; U-100% 15N] Grb7-SH2 domain-1, 0.6-0.8 mM [U-100% 13C; U-100% 15N] pY1139 peptide-2, 52.2 mM acetic acid-3, 100 mM sodium chloride-4, 5 mM DTT-5, 1 mM EDTA-6, 0.9 mM sodium azide-7, 90% H2O/10% D2O
Solvent system: 90% H2O/10% D2O
Sample
Conc. (mg/ml)UnitsComponentIsotopic labelingConc. range (mg/ml)Solution-ID
mMGrb7-SH2 domain-1[U-100% 13C; U-100% 15N]0.6-0.81
mMpY1139 peptide-2[U-100% 13C; U-100% 15N]0.6-0.81
52.2 mMacetic acid-31
100 mMsodium chloride-41
5 mMDTT-51
1 mMEDTA-61
0.9 mMsodium azide-71
Sample conditionspH: 6.6 / Pressure: ambient / Temperature: 298 K

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NMR measurement

NMR spectrometerType: Varian INOVA / Manufacturer: Varian / Model: INOVA / Field strength: 500 MHz

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Processing

NMR software
NameVersionDeveloperClassification
Amber9Case, Darden, Cheatham, III, Simmerling, Wang, Duke, Luo, ... and Kollmrefinement
CNS1.1Brunger, Adams, Clore, Gros, Nilges and Readstructure calculation
RefinementMethod: molecular dynamics simulated annealing, simulated annealing
Software ordinal: 1
Details: Refinement with AMBER software, using implicit water (generalized Born model) and ff99SB force field, Structure calculation with CNS software, in vacuum
NMR representativeSelection criteria: best procheck statistics
NMR ensembleConformer selection criteria: structures with the lowest energy and the fewest restraint violations
Conformers calculated total number: 50 / Conformers submitted total number: 10

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