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- PDB-5n7e: Crystal structure of the Dbl-homology domain of Bcr-Abl in comple... -

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Basic information

Entry
Database: PDB / ID: 5n7e
TitleCrystal structure of the Dbl-homology domain of Bcr-Abl in complex with monobody Mb(Bcr-DH_4).
Components
  • Breakpoint cluster region protein
  • Mb(Bcr-DH_4)
KeywordsSIGNALING PROTEIN / Dbl-homology / monobody / Bcr-Abl / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Breakpoint cluster region protein
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.647 Å
AuthorsReckel, S. / Reynaud, A. / Pojer, F. / Hantschel, O.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation31003A_140913 Switzerland
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 20, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mb(Bcr-DH_4)
B: Breakpoint cluster region protein


Theoretical massNumber of molelcules
Total (without water)35,0232
Polymers35,0232
Non-polymers00
Water6,269348
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area820 Å2
ΔGint-8 kcal/mol
Surface area14500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)164.122, 55.568, 45.031
Angle α, β, γ (deg.)90.000, 105.460, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-962-

HOH

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Components

#1: Protein Mb(Bcr-DH_4)


Mass: 10121.201 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#2: Protein Breakpoint cluster region protein / Renal carcinoma antigen NY-REN-26


Mass: 24901.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCR, BCR1, D22S11 / Plasmid: pETM-11 / Production host: Escherichia coli (E. coli)
References: UniProt: P11274, non-specific serine/threonine protein kinase
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 348 / 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: 2.83 Å3/Da / Density % sol: 56.47 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.12 M monosaccharides (0.2M D-Glucose; 0.2M D-Mannose; 0.2M D-Galactose; 0.2M L-Fucose; 0.2M D-Xylose; 0.2M N-Acetyl-D-Glucosamine); 0.1 M buffer system 2 pH 7.5 (Sodium HEPES; MOPS (acid)); ...Details: 0.12 M monosaccharides (0.2M D-Glucose; 0.2M D-Mannose; 0.2M D-Galactose; 0.2M L-Fucose; 0.2M D-Xylose; 0.2M N-Acetyl-D-Glucosamine); 0.1 M buffer system 2 pH 7.5 (Sodium HEPES; MOPS (acid)); 50% precipitant mix 1 (40% v/v PEG 500* MME; 20 % w/v PEG 20000)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.99987 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Aug 21, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.647→43.402 Å / Num. obs: 47055 / % possible obs: 99.27 % / Redundancy: 3.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.03673 / Rpim(I) all: 0.02165 / Net I/σ(I): 18.29
Reflection shellResolution: 1.647→1.706 Å / Rmerge(I) obs: 0.5916 / Mean I/σ(I) all: 1.94 / Num. unique all: 4391 / CC1/2: 0.946 / Rpim(I) all: 0.3474 / % possible all: 93.25

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
PDB_EXTRACT3.22data extraction
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Chain A: homology model based on 4JE4, Chain B: homology model based on 2Z0Q

4je4

2z0q


Resolution: 1.647→43.402 Å / SU ML: 0.21 / Cross valid method: NONE / σ(F): 1.35 / Phase error: 23.2
RfactorNum. reflection% reflection
Rfree0.2194 2451 5.21 %
Rwork0.1833 --
obs0.1852 47055 99.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 101.18 Å2 / Biso mean: 36.1086 Å2 / Biso min: 15.49 Å2
Refinement stepCycle: final / Resolution: 1.647→43.402 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2200 0 0 348 2548
Biso mean---43.7 -
Num. residues----279
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062317
X-RAY DIFFRACTIONf_angle_d0.8083172
X-RAY DIFFRACTIONf_chiral_restr0.054363
X-RAY DIFFRACTIONf_plane_restr0.006406
X-RAY DIFFRACTIONf_dihedral_angle_d14.1451413
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 18

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6474-1.67910.31781420.29652174231688
1.6791-1.71330.29041290.273924552584100
1.7133-1.75060.25911470.268424702617100
1.7506-1.79130.30771280.256225312659100
1.7913-1.83610.25721260.245524482574100
1.8361-1.88580.25731290.225425192648100
1.8858-1.94120.20861120.221324652577100
1.9412-2.00390.25391380.211724822620100
2.0039-2.07550.24981570.213424772634100
2.0755-2.15860.26111280.207525122640100
2.1586-2.25690.22371380.209524702608100
2.2569-2.37580.22781270.197625082635100
2.3758-2.52470.22431550.200124762631100
2.5247-2.71960.27391480.194524752623100
2.7196-2.99320.23961220.186425472669100
2.9932-3.42620.23171450.169924972642100
3.4262-4.3160.1731360.150825242660100
4.316-43.41710.18591440.152525742718100

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