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

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Basic information

Entry
Database: PDB / ID: 1opj
TitleStructural basis for the auto-inhibition of c-Abl tyrosine kinase
ComponentsProto-oncogene tyrosine-protein kinase ABL1
KeywordsTRANSFERASE
Function / homology
Function and homology information


Role of ABL in ROBO-SLIT signaling / HDR through Single Strand Annealing (SSA) / RHO GTPases Activate WASPs and WAVEs / Cyclin D associated events in G1 / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / circulatory system development / podocyte apoptotic process / DN4 thymocyte differentiation ...Role of ABL in ROBO-SLIT signaling / HDR through Single Strand Annealing (SSA) / RHO GTPases Activate WASPs and WAVEs / Cyclin D associated events in G1 / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / circulatory system development / podocyte apoptotic process / DN4 thymocyte differentiation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / response to epinephrine / regulation of cellular senescence / transitional one stage B cell differentiation / regulation of modification of synaptic structure / Regulation of actin dynamics for phagocytic cup formation / delta-catenin binding / B cell proliferation involved in immune response / positive regulation of extracellular matrix organization / neuroepithelial cell differentiation / microspike assembly / positive regulation of Wnt signaling pathway, planar cell polarity pathway / regulation of extracellular matrix organization / cerebellum morphogenesis / positive regulation of blood vessel branching / B-1 B cell homeostasis / neuropilin signaling pathway / neuropilin binding / Myogenesis / bubble DNA binding / activated T cell proliferation / regulation of Cdc42 protein signal transduction / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / syntaxin binding / alpha-beta T cell differentiation / cardiac muscle cell proliferation / regulation of T cell differentiation / regulation of axon extension / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cell-cell adhesion / cell leading edge / B cell proliferation / regulation of microtubule polymerization / positive regulation of osteoblast proliferation / platelet-derived growth factor receptor-beta signaling pathway / negative regulation of cellular senescence / positive regulation of focal adhesion assembly / associative learning / Bergmann glial cell differentiation / neuromuscular process controlling balance / platelet-derived growth factor receptor signaling pathway / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / negative regulation of long-term synaptic potentiation / endothelial cell migration / positive regulation of T cell migration / canonical NF-kappaB signal transduction / signal transduction in response to DNA damage / negative regulation of double-strand break repair via homologous recombination / BMP signaling pathway / phagocytosis / negative regulation of endothelial cell apoptotic process / four-way junction DNA binding / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of vasoconstriction / spleen development / positive regulation of stress fiber assembly / cellular response to transforming growth factor beta stimulus / ruffle / positive regulation of establishment of T cell polarity / ERK1 and ERK2 cascade / positive regulation of interleukin-2 production / ephrin receptor binding / actin filament polymerization / phosphotyrosine residue binding / response to endoplasmic reticulum stress / positive regulation of mitotic cell cycle / SH2 domain binding / substrate adhesion-dependent cell spreading / positive regulation of release of sequestered calcium ion into cytosol / post-embryonic development / thymus development / neural tube closure / establishment of localization in cell / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / protein kinase C binding / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / neuron differentiation / epidermal growth factor receptor signaling pathway / negative regulation of ERK1 and ERK2 cascade / autophagy / cell-cell adhesion / SH3 domain binding / cellular response to hydrogen peroxide
Similarity search - Function
F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains ...F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
MYRISTIC ACID / Chem-STI / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 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.
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
Revision 1.3Aug 16, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details
Remark 999SEQUENCE Myristoylated peptide (MYR)GQQPGKVLGDQRRPSL was crystallized in complex with the kinase ...SEQUENCE Myristoylated peptide (MYR)GQQPGKVLGDQRRPSL was crystallized in complex with the kinase domain. This sequence corresponds to the N-terminal 16 residues of mouse C-ABL(isoform IV). However, only the myristoyl portion of the peptide has density and all residues beyond the myristoyl group are disordered, therefore they are not 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 peptide. Residues numbering for the chains A and B corresponds to the sequence database numbering of the isoform IV of 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 ABL1
B: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,0028
Polymers67,4872
Non-polymers1,5156
Water4,161231
1
A: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5014
Polymers33,7441
Non-polymers7573
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5014
Polymers33,7441
Non-polymers7573
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.844, 63.507, 64.051
Angle α, β, γ (deg.)67.91, 79.76, 84.88
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase ABL1 / p150 / c-ABL


Mass: 33743.523 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: ABL1 / Plasmid: PFASTBAC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P00520, EC: 2.7.1.112
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
Details: THIS SEQUENCE CORRESPONDS TO THE N-TERMINAL 16 RESIDUES OF MOUSE C-ABL (ISOFORM IV)
#3: Chemical ChemComp-MYR / MYRISTIC ACID


Mass: 228.371 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H28O2
#4: Chemical ChemComp-STI / 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE / STI-571 / IMATINIB


Mass: 493.603 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H31N7O / Comment: medication, inhibitor*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / 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: 2.22 Å3/Da / Density % sol: 44.06 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 22% PEG 4000, 100 mM MES pH 5.6, 200 mM magnesium chloride, VAPOR DIFFUSION, HANGING DROP, temperature 277K
Crystal grow
*PLUS
Temperature: 4 ℃ / pH: 8
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
122 %(w/v)PEG40001reservoir
2100 mMMES1reservoirpH5.6
3200 mM1reservoirMgCl2
420 mMTris-HCl1droppH8.0
5100 mM1dropNaCl
65 mMdithiothreitol1drop
735 mg/mlprotein1drop

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.934 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jul 10, 2002 / Details: Sagitally focusing Ge(220) and a multilayer
RadiationMonochromator: Diamond (111), Ge(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.934 Å / Relative weight: 1
ReflectionResolution: 1.7→30 Å / Num. all: 61592 / Num. obs: 61592 / % possible obs: 92.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.4 % / Biso Wilson estimate: 21.6 Å2 / Rsym value: 0.09 / Net I/σ(I): 9.41
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 3.6 % / Mean I/σ(I) obs: 2.84 / Num. unique all: 7906 / Rsym value: 0.509 / % possible all: 75.8
Reflection
*PLUS
Lowest resolution: 30 Å / Num. measured all: 268488 / Rmerge(I) obs: 0.09
Reflection shell
*PLUS
Highest resolution: 1.7 Å / Lowest resolution: 1.8 Å / % possible obs: 75.8 % / Rmerge(I) obs: 0.509 / Mean I/σ(I) obs: 2.8

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Processing

Software
NameVersionClassification
CNS1.1refinement
XDSdata reduction
XSCALEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1IEP

1iep


Resolution: 1.75→29.41 Å / Rfactor Rfree error: 0.005 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.242 2886 5 %RANDOM
Rwork0.21 ---
obs0.21 57712 95.2 %-
all-57712 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 31.7556 Å2 / ksol: 0.363517 e/Å3
Displacement parametersBiso mean: 30 Å2
Baniso -1Baniso -2Baniso -3
1-0.83 Å21.1 Å22.57 Å2
2--1.36 Å2-3.22 Å2
3----2.19 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.26 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.2 Å0.16 Å
Refinement stepCycle: LAST / Resolution: 1.75→29.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4664 0 106 231 5001
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d21.8
X-RAY DIFFRACTIONc_improper_angle_d0.87
X-RAY DIFFRACTIONc_mcbond_it1.391.5
X-RAY DIFFRACTIONc_mcangle_it2.232
X-RAY DIFFRACTIONc_scbond_it1.972
X-RAY DIFFRACTIONc_scangle_it2.952.5
LS refinement shellResolution: 1.75→1.86 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.307 439 5 %
Rwork0.275 8353 -
obs-8353 87.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAM&_1_TOPOLOGY_INFILE_1
X-RAY DIFFRACTION2STIPIPFLIP.PAR&_1_TOPOLOGY_INFILE_2
X-RAY DIFFRACTION3WATER_REP.PARAM&_1_TOPOLOGY_INFILE_3
X-RAY DIFFRACTION4MYR.PAR&_1_TOPOLOGY_INFILE_4
X-RAY DIFFRACTION5ION.PARAM&_1_TOPOLOGY_INFILE_5
Refinement
*PLUS
Highest resolution: 1.7 Å / Lowest resolution: 30 Å / Rfactor Rwork: 0.21
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg21.8
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.87
LS refinement shell
*PLUS
Highest resolution: 1.7 Å / Lowest resolution: 1.8 Å

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