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- PDB-1opl: Structural basis for the auto-inhibition of c-Abl tyrosine kinase -

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Basic information

Entry
Database: PDB / ID: 1opl
TitleStructural basis for the auto-inhibition of c-Abl tyrosine kinase
Componentsproto-oncogene tyrosine-protein kinase
KeywordsTRANSFERASE
Function / homology
Function and homology information


Role of ABL in ROBO-SLIT signaling / Regulation of actin dynamics for phagocytic cup formation / Myogenesis / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Factors involved in megakaryocyte development and platelet production / RUNX2 regulates osteoblast differentiation / Cyclin D associated events in G1 / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / HDR through Single Strand Annealing (SSA) / RHO GTPases Activate WASPs and WAVEs ...Role of ABL in ROBO-SLIT signaling / Regulation of actin dynamics for phagocytic cup formation / Myogenesis / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Factors involved in megakaryocyte development and platelet production / RUNX2 regulates osteoblast differentiation / Cyclin D associated events in G1 / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / HDR through Single Strand Annealing (SSA) / RHO GTPases Activate WASPs and WAVEs / mitochondrial depolarization / transitional one stage B cell differentiation / positive regulation of actin filament binding / DNA conformation change / activation of protein kinase C activity / negative regulation of phospholipase C activity / actin filament branching / positive regulation of interleukin-2 secretion / positive regulation blood vessel branching / nicotinate-nucleotide adenylyltransferase activity / B cell proliferation involved in immune response / positive regulation of microtubule binding / neuroepithelial cell differentiation / positive regulation of Wnt signaling pathway, planar cell polarity pathway / regulation of extracellular matrix organization / microspike assembly / regulation of modification of synaptic structure / cerebellum morphogenesis / collateral sprouting / B-1 B cell homeostasis / cardiovascular system development / alpha-beta T cell differentiation / positive regulation of oxidoreductase activity / activated T cell proliferation / bubble DNA binding / neuropilin signaling pathway / neuropilin binding / regulation of T cell differentiation / regulation of Cdc42 protein signal transduction / negative regulation of protein serine/threonine kinase activity / negative regulation of ubiquitin-protein transferase activity / regulation of microtubule polymerization / regulation of actin cytoskeleton reorganization / negative regulation of BMP signaling pathway / mitogen-activated protein kinase binding / sequence-specific double-stranded DNA binding / proline-rich region binding / positive regulation of interferon-gamma secretion / negative regulation of cell-cell adhesion / cellular response to dopamine / syntaxin binding / regulation of response to DNA damage stimulus / DNA damage induced protein phosphorylation / negative regulation of cellular senescence / positive regulation of osteoblast proliferation / cell leading edge / regulation of axon extension / actin monomer binding / positive regulation of cell migration involved in sprouting angiogenesis / platelet-derived growth factor receptor-beta signaling pathway / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / Bergmann glial cell differentiation / mismatch repair / regulation of hematopoietic stem cell differentiation / positive regulation of focal adhesion assembly / positive regulation of muscle cell differentiation / positive regulation of actin cytoskeleton reorganization / regulation of endocytosis / regulation of cell adhesion / negative regulation of mitotic cell cycle / positive regulation of substrate adhesion-dependent cell spreading / regulation of cell motility / negative regulation of endothelial cell apoptotic process / four-way junction DNA binding / endothelial cell migration / positive regulation of stress fiber assembly / regulation of actin cytoskeleton organization / signal transduction in response to DNA damage / substrate adhesion-dependent cell spreading / regulation of autophagy / positive regulation of endothelial cell migration / cellular protein modification process / spleen development / SH2 domain binding / post-embryonic development / neural tube closure / positive regulation of mitotic cell cycle / negative regulation of I-kappaB kinase/NF-kappaB signaling / positive regulation of release of sequestered calcium ion into cytosol / thymus development / protein kinase C binding / negative regulation of ERK1 and ERK2 cascade / phosphotyrosine residue binding / ephrin receptor binding / integrin-mediated signaling pathway / actin cytoskeleton organization / autophagy / non-specific protein-tyrosine kinase / peptidyl-tyrosine autophosphorylation
Tyrosine-protein kinase ABL1/transforming protein Abl / Protein tyrosine kinase / Protein kinase, ATP binding site / Src homology 3 (SH3) domain profile. / Src homology 2 (SH2) domain profile. / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein kinases ATP-binding region signature. / F-actin binding / SH3 domain ...Tyrosine-protein kinase ABL1/transforming protein Abl / Protein tyrosine kinase / Protein kinase, ATP binding site / Src homology 3 (SH3) domain profile. / Src homology 2 (SH2) domain profile. / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein kinases ATP-binding region signature. / F-actin binding / SH3 domain / SH2 domain / SH2 domain superfamily / SH3-like domain superfamily / Tyrosine-protein kinase ABL, SH2 domain / Protein kinase-like domain superfamily / Tyrosine-protein kinase, catalytic domain / Protein kinase domain / Protein kinase domain profile. / Serine-threonine/tyrosine-protein kinase, catalytic domain / SH2 domain / SH3 domain / F-actin binding
Tyrosine-protein kinase ABL1
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.42 Å
AuthorsNagar, B. / Hantschel, O. / Young, M.A. / Scheffzek, K. / Veach, D. / Bornmann, W. / Clarkson, B. / Superti-Furga, G. / Kuriyan, J.
Citation
Journal: Cell(Cambridge,Mass.) / Year: 2003
Title: Structural basis for the autoinhibition of c-Abl tyrosine kinase
Authors: Nagar, B. / Hantschel, O. / Young, M.A. / Scheffzek, K. / Veach, D. / Bornmann, W. / Clarkson, B. / Superti-Furga, G. / Kuriyan, J.
#1: Journal: Cell(Cambridge,Mass.) / Year: 2003
Title: A myristoyl/phosphotyrosine switch regulates c-Abl
Authors: Hantschel, O. / Nagar, B. / Guettler, S. / Kretzschmar, J. / Dorey, K. / Kuriyan, J. / Superti-Furga, G.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMar 6, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Remark 999SEQUENCE The bound myristoyl group is from the naturally occurring N-terminal myristoyl ...SEQUENCE The bound myristoyl group is from the naturally occurring N-terminal myristoyl modification that is connected to the SH3 domain of the protein chain A by 79 residues that could not be modeled. An O atom has been intentionally omitted from MYR since the O atom is not chemically present in a myristoyl group that is attached to the protein.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: proto-oncogene tyrosine-protein kinase
B: proto-oncogene tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,1225
Polymers122,0392
Non-polymers1,0833
Water0
1
A: proto-oncogene tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,6753
Polymers61,0201
Non-polymers6562
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: proto-oncogene tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,4472
Polymers61,0201
Non-polymers4271
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
A: proto-oncogene tyrosine-protein kinase
hetero molecules

A: proto-oncogene tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,3516
Polymers122,0392
Non-polymers1,3114
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_655-x+1,y,-z+1/21
Buried area5100 Å2
ΔGint-33 kcal/mol
Surface area40710 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)77.017, 273.384, 124.384
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein/peptide proto-oncogene tyrosine-protein kinase


Mass: 61019.672 Da / Num. of mol.: 2
Fragment: N-terminal 531 residues (MYR-SH3-SH2-Kinase domain)
Mutation: D382N, K29R, E29D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: Abl / Plasmid: PFASTBAC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P00519, EC: 2.7.1.112
#2: Chemical ChemComp-MYR / MYRISTIC ACID


Mass: 228.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H28O2 / Myristic acid
#3: Chemical ChemComp-P16 / 6-(2,6-DICHLOROPHENYL)-2-{[3-(HYDROXYMETHYL)PHENYL]AMINO}-8-METHYLPYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE / PD166326


Mass: 427.283 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H16Cl2N4O2

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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: 2.68 Å3/Da / Density % sol: 54.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.8 M ammonium tartrate , pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K
Crystal grow
*PLUS
Temperature: 20 ℃ / pH: 8
Components of the solutions
*PLUS

Crystal-ID: 1

IDConc.Common nameSol-IDDetailsChemical formula
10.8 mMammonium tartratereservoir
220 mMTris-HCldroppH8.0
3100 mMdropNaCl
45 mMdithiothreitoldrop
535 mg/mlproteindrop

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 13, 2002 / Details: mirrors
RadiationMonochromator: Double Crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.4→75 Å / Num. all: 17250 / Num. obs: 17250 / % possible obs: 95.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 6.1 % / Biso Wilson estimate: 84.8 Å2 / Rsym value: 0.081 / Net I/σ(I): 19.7
Reflection shellResolution: 3.4→3.52 Å / Redundancy: 5.2 % / Mean I/σ(I) obs: 3.4 / Num. unique all: 1617 / Rsym value: 0.465 / % possible all: 91.4
Reflection
*PLUS
Lowest resolution: 75 Å / Num. measured all: 105428 / Rmerge(I) obs: 0.081
Reflection shell
*PLUS
Highest resolution: 3.4 Å / % possible obs: 91.4 % / Rmerge(I) obs: 0.465

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Processing

Software
NameVersionClassification
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRIES 1M52, 2ABL
Resolution: 3.42→29.95 Å / Rfactor Rfree error: 0.009 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: The structure was refined by superimposing the refined high resolution structure of c-Abl (pdb entry 1OPK) on the molecular replacement solution and optimizing positions of individual domains by rigid-body refinement. Following this, only overall domain B-factors were applied to molecule B, whereas individual B-factors were refined for molecule A.
RfactorNum. reflection% reflectionSelection details
Rfree0.315 1106 6.8 %RANDOM
Rwork0.306 ---
Obs0.306 16203 89.1 %-
All-16203 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 59.717 Å2 / ksol: 0.277405 e/Å3
Displacement parametersBiso mean: 123.3 Å2
Baniso -1Baniso -2Baniso -3
1--19.23 Å20 Å20 Å2
2--20.33 Å20 Å2
3----1.11 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.53 Å0.5 Å
Luzzati d res low-5 Å
Luzzati sigma a0.45 Å0.44 Å
Refinement stepCycle: LAST / Resolution: 3.42→29.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6582 0 73 0 6655
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal target
c_bond_d0.01
c_angle_deg1.6
c_dihedral_angle_d23.2
c_improper_angle_d1.05
c_mcbond_it3.451.5
c_mcangle_it5.972
c_scbond_it5.532
c_scangle_it9.082.5
LS refinement shellResolution: 3.4→3.61 Å / Rfactor Rfree error: 0.03 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.333 121 5.8 %
Rwork0.319 1965 -
Obs-1965 69.1 %
Xplor file

Refinement-ID: X-RAY DIFFRACTION

Serial noParam fileTopol file
1PROTEIN_REP.PARAM&_1_TOPOLOGY_INFILE_1
2P16.PAR&_1_TOPOLOGY_INFILE_2
3MYR.PAR&_1_TOPOLOGY_INFILE_3
4&_1_PARAMETER_INFILE_4&_1_TOPOLOGY_INFILE_4
5&_1_PARAMETER_INFILE_5&_1_TOPOLOGY_INFILE_5
Refinement
*PLUS
Highest resolution: 3.4 Å / Lowest resolution: 75 Å
Refine LS restraints
*PLUS
Refinement-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg23.2
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.05
LS refinement shell
*PLUS
Highest resolution: 3.4 Å / Lowest resolution: 3.52 Å

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