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- PDB-3cs9: Human ABL kinase in complex with nilotinib -

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Basic information

Entry
Database: PDB / ID: 3cs9
TitleHuman ABL kinase in complex with nilotinib
ComponentsProto-oncogene tyrosine-protein kinase ABL1
KeywordsTRANSFERASE / nilotinib / amn107 / kinase / Abl / Alternative splicing / ATP-binding / Cell adhesion / Chromosomal rearrangement / Cytoplasm / Cytoskeleton / Lipoprotein / Magnesium / Manganese / Metal-binding / Myristate / Nucleotide-binding / Nucleus / Phosphoprotein / Polymorphism / Proto-oncogene / SH2 domain / SH3 domain / Tyrosine-protein kinase / ABL KINASE WT IN COMPLEX WITH NVP-AMN107
Function / homology
Function and homology information


negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / transitional one stage B cell differentiation / positive regulation of phospholipase C/protein kinase C signal transduction / regulation of postsynaptic specialization assembly ...negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / transitional one stage B cell differentiation / positive regulation of phospholipase C/protein kinase C signal transduction / regulation of postsynaptic specialization assembly / regulation of modification of synaptic structure / nicotinate-nucleotide adenylyltransferase activity / delta-catenin binding / cerebellum morphogenesis / Role of ABL in ROBO-SLIT signaling / B cell proliferation involved in immune response / neuroepithelial cell differentiation / positive regulation of extracellular matrix organization / positive regulation of Wnt signaling pathway, planar cell polarity pathway / microspike assembly / B-1 B cell homeostasis / neuropilin signaling pathway / neuropilin binding / mitochondrial depolarization / regulation of cell motility / bubble DNA binding / positive regulation of establishment of T cell polarity / cellular response to dopamine / activated T cell proliferation / positive regulation of blood vessel branching / proline-rich region binding / negative regulation of mitotic cell cycle / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / regulation of hematopoietic stem cell differentiation / positive regulation of dendrite development / syntaxin binding / regulation of axon extension / regulation of T cell differentiation / alpha-beta T cell differentiation / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cell-cell adhesion / neuromuscular process controlling balance / Myogenesis / HDR through Single Strand Annealing (SSA) / positive regulation of osteoblast proliferation / platelet-derived growth factor receptor-beta signaling pathway / RUNX2 regulates osteoblast differentiation / Fc-gamma receptor signaling pathway involved in phagocytosis / vascular endothelial cell response to oscillatory fluid shear stress / Bergmann glial cell differentiation / regulation of endocytosis / myoblast proliferation / regulation of microtubule polymerization / negative regulation of long-term synaptic potentiation / negative regulation of cellular senescence / associative learning / positive regulation of vasoconstriction / actin monomer binding / negative regulation of BMP signaling pathway / positive regulation of focal adhesion assembly / cardiac muscle cell proliferation / RHO GTPases Activate WASPs and WAVEs / ephrin receptor signaling pathway / BMP signaling pathway / cellular response to transforming growth factor beta stimulus / negative regulation of endothelial cell apoptotic process / positive regulation of T cell migration / endothelial cell migration / negative regulation of double-strand break repair via homologous recombination / canonical NF-kappaB signal transduction / regulation of cell adhesion / positive regulation of interleukin-2 production / mismatch repair / ephrin receptor binding / spleen development / four-way junction DNA binding / positive regulation of stress fiber assembly / ruffle / ERK1 and ERK2 cascade / signal transduction in response to DNA damage / phosphotyrosine residue binding / actin filament polymerization / positive regulation of substrate adhesion-dependent cell spreading / substrate adhesion-dependent cell spreading / positive regulation of mitotic cell cycle / positive regulation of endothelial cell migration / SH2 domain binding / response to endoplasmic reticulum stress / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / protein kinase C binding / positive regulation of release of sequestered calcium ion into cytosol / thymus development / establishment of localization in cell / integrin-mediated signaling pathway / B cell receptor signaling pathway / protein serine/threonine kinase activator activity / post-embryonic development / protein modification process / regulation of actin cytoskeleton organization
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 ...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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
Nilotinib / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.21 Å
AuthorsCowan-Jacob, S.W. / Fendrich, G. / Manley, P. / Liebetanz, J. / Fabbro, D.
Citation
Journal: Cancer Cell / Year: 2005
Title: Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl
Authors: Weisberg, E. / Manley, P.W. / Breitenstein, W. / Brueggen, J. / Cowan-Jacob, S.W. / Ray, A. / Huntly, B. / Fabbro, D. / Fendrich, G. / Hall-Meyers, E. / Kung, A.L. / Mestan, J. / Daley, G.Q. ...Authors: Weisberg, E. / Manley, P.W. / Breitenstein, W. / Brueggen, J. / Cowan-Jacob, S.W. / Ray, A. / Huntly, B. / Fabbro, D. / Fendrich, G. / Hall-Meyers, E. / Kung, A.L. / Mestan, J. / Daley, G.Q. / Callahan, L. / Catley, L. / Cavazza, C. / Azam, M. / Neuberg, D. / Wright, R.D. / Gilliland, D.G. / Griffin, J.D.
#1: Journal: To be Published
Title: Solution conformations and dynamics of ABL kinase inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib
Authors: Vajpai, N. / Strauss, A. / Fendrich, G. / Cowan-Jacob, S.W. / Manley, P.W. / Grzesiek, S. / Jahnke, W.
History
DepositionApr 9, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._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 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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
C: Proto-oncogene tyrosine-protein kinase ABL1
D: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,3218
Polymers128,2034
Non-polymers2,1184
Water4,792266
1
A: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5802
Polymers32,0511
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5802
Polymers32,0511
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5802
Polymers32,0511
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5802
Polymers32,0511
Non-polymers5301
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.926, 118.088, 123.683
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Proto-oncogene tyrosine-protein kinase ABL1 / p150 / c-ABL / Abelson murine leukemia viral oncogene homolog 1


Mass: 32050.684 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN (UNP residues 229-500)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-NIL / Nilotinib / 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide


Mass: 529.516 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H22F3N7O / Comment: medication, anticancer*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 266 / 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: 2.68 Å3/Da / Density % sol: 54.02 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 10.5 % PEG 5000 MME, 0.1 M MES pH 5.5, 0.05 ammonium acetate, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00033 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jan 29, 2004
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00033 Å / Relative weight: 1
ReflectionResolution: 2.2→40 Å / Num. all: 68942 / Num. obs: 68942 / % possible obs: 98.58 % / Redundancy: 7.53 % / Rmerge(I) obs: 0.056
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 6.25 % / Rmerge(I) obs: 0.401 / Num. unique all: 6728 / % possible all: 97.1

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Processing

Software
NameVersionClassification
REFMAC5.1.9999refinement
DENZOdata reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: Unpublished structure of Abl complex

Resolution: 2.21→40 Å / SU B: 11.228 / SU ML: 0.143 / Cross valid method: THROUGHOUT / ESU R: 0.237 / ESU R Free: 0.199 / Stereochemistry target values: Engh & Huber / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24186 3477 5 %RANDOM
Rwork0.19744 ---
all0.19965 65406 --
obs0.19965 65406 98.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 46.122 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20 Å2
2--0.58 Å20 Å2
3----0.59 Å2
Refine analyzeLuzzati coordinate error free: 0.199 Å
Refinement stepCycle: LAST / Resolution: 2.21→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8274 0 156 266 8696
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0228659
X-RAY DIFFRACTIONr_bond_other_d0.0020.027677
X-RAY DIFFRACTIONr_angle_refined_deg1.5941.96311732
X-RAY DIFFRACTIONr_angle_other_deg1.035317844
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.54451003
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.39224.116396
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.245151483
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8271541
X-RAY DIFFRACTIONr_chiral_restr0.0920.21230
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.029477
X-RAY DIFFRACTIONr_gen_planes_other0.010.021836
X-RAY DIFFRACTIONr_nbd_refined0.2150.21855
X-RAY DIFFRACTIONr_nbd_other0.190.27523
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0920.24422
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.170.2334
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2330.239
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2560.294
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.240.212
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2171.55548
X-RAY DIFFRACTIONr_mcbond_other0.2361.52054
X-RAY DIFFRACTIONr_mcangle_it1.66428165
X-RAY DIFFRACTIONr_scbond_it2.29734208
X-RAY DIFFRACTIONr_scangle_it3.2454.53567
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.21→2.263 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.313 268
Rwork0.237 4633

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