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- PDB-5oc7: Crystal structure of the pleckstrin-homology domain of Bcr-Abl in... -

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Basic information

Entry
Database: PDB / ID: 5oc7
TitleCrystal structure of the pleckstrin-homology domain of Bcr-Abl in complex with monobody Mb(Bcr-PH_4).
Components
  • Breakpoint cluster region protein,pleckstrin-homology domain of Bcr-Abl
  • monobody Mb(Bcr-PH_4)
KeywordsSIGNALING PROTEIN / pleckstrin-homology / monobody / Bcr-Abl / phosphoinositide-binding
Function / homology
Function and homology information


negative regulation of respiratory burst / negative regulation of cellular extravasation / negative regulation of macrophage migration / neutrophil degranulation / negative regulation of blood vessel remodeling / negative regulation of neutrophil degranulation / macrophage migration / intracellular protein transmembrane transport / renal system process / regulation of vascular permeability ...negative regulation of respiratory burst / negative regulation of cellular extravasation / negative regulation of macrophage migration / neutrophil degranulation / negative regulation of blood vessel remodeling / negative regulation of neutrophil degranulation / macrophage migration / intracellular protein transmembrane transport / renal system process / regulation of vascular permeability / activation of GTPase activity / regulation of Rho protein signal transduction / focal adhesion assembly / definitive hemopoiesis / Signaling by cytosolic FGFR1 fusion mutants / regulation of small GTPase mediated signal transduction / inner ear morphogenesis / neuromuscular process controlling balance / RHOB GTPase cycle / small GTPase-mediated signal transduction / RHOC GTPase cycle / negative regulation of reactive oxygen species metabolic process / CDC42 GTPase cycle / homeostasis of number of cells / RHOA GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle / phagocytosis / keratinocyte differentiation / RAC1 GTPase cycle / Signaling by FGFR1 in disease / GTPase activator activity / positive regulation of phagocytosis / guanyl-nucleotide exchange factor activity / brain development / modulation of chemical synaptic transmission / negative regulation of inflammatory response / Schaffer collateral - CA1 synapse / cellular response to lipopolysaccharide / actin cytoskeleton organization / protein tyrosine kinase activity / dendritic spine / protein phosphorylation / non-specific serine/threonine protein kinase / regulation of cell cycle / postsynaptic density / axon / 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
Bcr-Abl oncoprotein oligomerisation / Bcr-Abl oncoprotein oligomerisation domain superfamily / Abr/Bcr / Bcr-Abl oncoprotein oligomerisation domain / PH domain / 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. ...Bcr-Abl oncoprotein oligomerisation / Bcr-Abl oncoprotein oligomerisation domain superfamily / Abr/Bcr / Bcr-Abl oncoprotein oligomerisation domain / PH domain / 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. / Protein kinase C conserved region 2 (CalB) / C2 domain / 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
D-MYO-INOSITOL-4,5-BISPHOSPHATE / Breakpoint cluster region protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.652 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
DepositionJun 29, 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
D: Breakpoint cluster region protein,pleckstrin-homology domain of Bcr-Abl
A: Breakpoint cluster region protein,pleckstrin-homology domain of Bcr-Abl
C: monobody Mb(Bcr-PH_4)
B: monobody Mb(Bcr-PH_4)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,53612
Polymers50,5524
Non-polymers9858
Water4,558253
1
A: Breakpoint cluster region protein,pleckstrin-homology domain of Bcr-Abl
C: monobody Mb(Bcr-PH_4)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6446
Polymers25,2762
Non-polymers3684
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
D: Breakpoint cluster region protein,pleckstrin-homology domain of Bcr-Abl
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,0753
Polymers15,6431
Non-polymers4322
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3920 Å2
ΔGint-4 kcal/mol
Surface area21400 Å2
MethodPISA
4
B: monobody Mb(Bcr-PH_4)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)9,8173
Polymers9,6331
Non-polymers1842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)29.683, 62.606, 67.378
Angle α, β, γ (deg.)62.74, 84.77, 89.29
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Breakpoint cluster region protein,pleckstrin-homology domain of Bcr-Abl / Renal carcinoma antigen NY-REN-26


Mass: 15643.062 Da / Num. of mol.: 2 / Mutation: delta 770-829,delta 770-829
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
#2: Protein monobody Mb(Bcr-PH_4)


Mass: 9632.773 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria)
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-IP2 / D-MYO-INOSITOL-4,5-BISPHOSPHATE


Mass: 340.116 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O12P2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 253 / 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: 2.47 Å3/Da / Density % sol: 50 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Potassium thiocyanate, 30% (w/v) PEG MME 2000

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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 / Detector: PIXEL / Date: May 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.652→33.68 Å / Num. obs: 49951 / % possible obs: 97.13 % / Redundancy: 4.899 % / Rmerge(I) obs: 0.03096 / Rpim(I) all: 0.01554 / Rrim(I) all: 0.03473 / Net I/σ(I): 23.01
Reflection shellResolution: 1.652→1.711 Å / Rmerge(I) obs: 0.6334 / Num. unique obs: 4899 / Rpim(I) all: 0.3281 / Rrim(I) all: 0.7159 / % possible all: 96.1

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2DFK

2dfk


Resolution: 1.652→33.68 Å / SU ML: 0.2 / Cross valid method: NONE / σ(F): 1.97 / Phase error: 21.66
RfactorNum. reflection% reflection
Rfree0.2043 2001 4 %
Rwork0.1742 --
obs0.1754 49948 95.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.652→33.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3212 0 62 253 3527
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0113420
X-RAY DIFFRACTIONf_angle_d1.0764646
X-RAY DIFFRACTIONf_dihedral_angle_d17.9472036
X-RAY DIFFRACTIONf_chiral_restr0.062529
X-RAY DIFFRACTIONf_plane_restr0.007576
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6516-1.67170.28241420.27243218X-RAY DIFFRACTION94
1.6717-1.69290.29191430.27913388X-RAY DIFFRACTION95
1.6929-1.71520.3191360.26953295X-RAY DIFFRACTION94
1.7152-1.73870.26981240.2553467X-RAY DIFFRACTION94
1.7387-1.76350.25581470.24723234X-RAY DIFFRACTION95
1.7635-1.78980.28151390.23993375X-RAY DIFFRACTION96
1.7898-1.81780.24381400.22413333X-RAY DIFFRACTION95
1.8178-1.84760.29121340.22613380X-RAY DIFFRACTION94
1.8476-1.87950.25821360.22723360X-RAY DIFFRACTION95
1.8795-1.91360.25181410.22023285X-RAY DIFFRACTION95
1.9136-1.95040.2391310.21083443X-RAY DIFFRACTION95
1.9504-1.99020.20271400.20663347X-RAY DIFFRACTION95
1.9902-2.03350.2481470.19263353X-RAY DIFFRACTION96
2.0335-2.08080.24151340.19893380X-RAY DIFFRACTION95
2.0808-2.13280.23651440.1873372X-RAY DIFFRACTION95
2.1328-2.19050.23121360.1933386X-RAY DIFFRACTION96
2.1905-2.25490.2191530.18493388X-RAY DIFFRACTION95
2.2549-2.32770.19221300.17683399X-RAY DIFFRACTION96
2.3277-2.41090.21091440.17713380X-RAY DIFFRACTION96
2.4109-2.50740.22221480.17913374X-RAY DIFFRACTION96
2.5074-2.62140.25381340.17233389X-RAY DIFFRACTION96
2.6214-2.75960.20591470.17373384X-RAY DIFFRACTION95
2.7596-2.93240.19741440.17163425X-RAY DIFFRACTION97
2.9324-3.15860.21131310.16313371X-RAY DIFFRACTION97
3.1586-3.47620.21251490.1623390X-RAY DIFFRACTION96
3.4762-3.97860.18271470.14953405X-RAY DIFFRACTION97
3.9786-5.00990.13821440.13013417X-RAY DIFFRACTION97
5.0099-33.69080.20761460.18813498X-RAY DIFFRACTION99

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