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- PDB-5n6r: Solution structure of the Dbl-homology domain of Bcr-Abl -

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Basic information

Entry
Database: PDB / ID: 5n6r
TitleSolution structure of the Dbl-homology domain of Bcr-Abl
ComponentsBreakpoint cluster region protein
KeywordsSIGNALING PROTEIN / Dbl-homology / helical bundle / Bcr-Abl / leukemia / transferase
Function / homology
Function and homology information


negative regulation of respiratory burst / negative regulation of cellular extravasation / negative regulation of macrophage migration / : / negative regulation of blood vessel remodeling / negative regulation of neutrophil degranulation / macrophage migration / neutrophil degranulation / intracellular protein transmembrane transport / renal system process ...negative regulation of respiratory burst / negative regulation of cellular extravasation / negative regulation of macrophage migration / : / negative regulation of blood vessel remodeling / negative regulation of neutrophil degranulation / macrophage migration / neutrophil degranulation / intracellular protein transmembrane transport / renal system process / regulation of vascular permeability / regulation of Rho protein signal transduction / focal adhesion assembly / definitive hemopoiesis / Signaling by cytosolic FGFR1 fusion mutants / activation of GTPase activity / regulation of small GTPase mediated signal transduction / inner ear morphogenesis / small GTPase-mediated signal transduction / RHOB GTPase cycle / RHOC GTPase cycle / CDC42 GTPase cycle / neuromuscular process controlling balance / homeostasis of number of cells / RHOA GTPase cycle / negative regulation of reactive oxygen species metabolic process / RAC2 GTPase cycle / RAC3 GTPase cycle / phagocytosis / positive regulation of phagocytosis / keratinocyte differentiation / RAC1 GTPase cycle / Signaling by FGFR1 in disease / GTPase activator activity / guanyl-nucleotide exchange factor activity / Schaffer collateral - CA1 synapse / brain development / modulation of chemical synaptic transmission / negative regulation of inflammatory response / actin cytoskeleton organization / protein tyrosine kinase activity / cellular response to lipopolysaccharide / dendritic spine / postsynaptic density / non-specific serine/threonine protein kinase / regulation of cell cycle / axon / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / glutamatergic synapse / signal transduction / protein-containing complex / extracellular exosome / ATP binding / membrane / plasma membrane / cytosol
Similarity search - Function
PH domain / Bcr-Abl oncoprotein oligomerisation / Bcr-Abl oncoprotein oligomerisation domain superfamily / Bcr-Abl oncoprotein oligomerisation domain / Abr/Bcr / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. ...PH domain / Bcr-Abl oncoprotein oligomerisation / Bcr-Abl oncoprotein oligomerisation domain superfamily / Bcr-Abl oncoprotein oligomerisation domain / Abr/Bcr / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / Rho GTPase activation protein / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / C2 domain / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain profile. / C2 domain superfamily / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily
Similarity search - Domain/homology
Breakpoint cluster region protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / TORSION ANGLE DYNAMICS ONFORMERS, NUMBER CALCULATED : NULL
AuthorsReckel, S. / Lohr, F. / Buchner, L. / Guntert, P. / Dotsch, V. / Hantschel, O.
Funding support Switzerland, Germany, 2items
OrganizationGrant numberCountry
Swiss National Science Foundation31003A_140913 Switzerland
European Union261863 Germany
CitationJournal: Nat Commun / Year: 2017
Title: Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase.
Authors: Sina Reckel / Charlotte Gehin / Delphine Tardivon / Sandrine Georgeon / Tim Kükenshöner / Frank Löhr / Akiko Koide / Lena Buchner / Alejandro Panjkovich / Aline Reynaud / Sara Pinho / ...Authors: Sina Reckel / Charlotte Gehin / Delphine Tardivon / Sandrine Georgeon / Tim Kükenshöner / Frank Löhr / Akiko Koide / Lena Buchner / Alejandro Panjkovich / Aline Reynaud / Sara Pinho / Barbara Gerig / Dmitri Svergun / Florence Pojer / Peter Güntert / Volker Dötsch / Shohei Koide / Anne-Claude Gavin / Oliver Hantschel /
Abstract: The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To ...The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To provide a molecular rationale for these observations, we study the Dbl-homology (DH) and Pleckstrin-homology (PH) domains of Bcr-Abl p210, which constitute the only structural differences to p190. Here we report high-resolution structures of the DH and PH domains and characterize conformations of the DH-PH unit in solution. Our structural and functional analyses show no evidence that the DH domain acts as a guanine nucleotide exchange factor, whereas the PH domain binds to various phosphatidylinositol-phosphates. PH-domain mutants alter subcellular localization and result in decreased interactions with p210-selective interaction partners. Hence, the PH domain, but not the DH domain, plays an important role in the formation of the differential p210 and p190 Bcr-Abl signaling networks.
History
DepositionFeb 16, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name
Revision 1.2May 8, 2019Group: Data collection / Category: database_PDB_remark / pdbx_nmr_software / Item: _database_PDB_remark.text / _pdbx_nmr_software.name
Revision 1.3Jun 14, 2023Group: Data collection / Database references / Other
Category: database_2 / pdbx_database_status / pdbx_nmr_spectrometer
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_nmr_data / _pdbx_nmr_spectrometer.model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Breakpoint cluster region protein


Theoretical massNumber of molelcules
Total (without water)24,8441
Polymers24,8441
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15380 Å2
MethodPISA
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)20 / 200target function
RepresentativeModel #1closest to the average

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Components

#1: Protein Breakpoint cluster region protein / Renal carcinoma antigen NY-REN-26


Mass: 24844.432 Da / Num. of mol.: 1 / Fragment: DH domain, UNP residues 487-702
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCR, BCR1, D22S11 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P11274, non-specific serine/threonine protein kinase

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D 1H-15N HSQC
121isotropic12D 1H-13C HSQC aliphatic
131isotropic42D 1H-13C HSQC aromatic
141isotropic13D HNCO
1111isotropic13D HN(CA)CO
151isotropic13D HN(CA)CB
1121isotropic13D HN(COCA)CB
181isotropic13D CCH-TOCSY
1131isotropic13D (H)CC(CO)NH-TOCSY
1141isotropic13D H(CCCO)NH-TOCSY
161isotropic53D HN(CA)HA
171isotropic53D 1H-13C NOESY
1101isotropic33D 1H-15N NOESY
1151isotropic12D 1H-13C HSQC aromatic
1161isotropic12D 1H-13C HSQC aromatic
1171isotropic22D 1H-1H COSY
1181isotropic22D 1H-1H TOCSY
NMR detailsText: NULL

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Sample preparation

DetailsType: solution / Contents: 0.85 mM [U-13C; U-15N] DH, 90% H2O/10% D2O / Label: 15N,13C_sample / Solvent system: 90% H2O/10% D2O
SampleConc.: 0.85 mM / Component: DH / Isotopic labeling: [U-13C; U-15N]
Sample conditionsIonic strength: 0.05 M / Label: conditions_1 / pH: 7.0 / Pressure: AMBIENT Pa / Temperature: 303 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCEBrukerAVANCE6001
Bruker AVANCEBrukerAVANCE7002
Bruker AVANCEBrukerAVANCE8003
Bruker AVANCEBrukerAVANCE9004
Bruker AVANCEBrukerAVANCE9505

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Processing

NMR software
NameDeveloperClassification
CYANAGuntert P.structure calculation
SparkyGoddardchemical shift assignment
FLYAGuntert P.chemical shift assignment
TopSpinBruker Biospincollection
RefinementMethod: TORSION ANGLE DYNAMICS ONFORMERS, NUMBER CALCULATED : NULL
Software ordinal: 1
NMR representativeSelection criteria: closest to the average
NMR ensembleConformer selection criteria: target function / Conformers calculated total number: 200 / Conformers submitted total number: 20

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