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- PDB-4wa9: The crystal structure of human abl1 wild type kinase domain in co... -

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Basic information

Entry
Database: PDB / ID: 4wa9
TitleThe crystal structure of human abl1 wild type kinase domain in complex with axitinib
ComponentsTyrosine-protein kinase ABL1
KeywordsTransferase/Transferase Inhibitor / KINASE / KINASE INHIBITOR / AXITINIB / ACTIVATION LOOP / DFG-OUT / TRANSFERASE / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / delta-catenin binding ...positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / delta-catenin binding / Role of ABL in ROBO-SLIT signaling / transitional one stage B cell differentiation / regulation of postsynaptic specialization assembly / regulation of modification of synaptic structure / nicotinate-nucleotide adenylyltransferase activity / DNA conformation change / neuroepithelial cell differentiation / : / B cell proliferation involved in immune response / cerebellum morphogenesis / positive regulation of Wnt signaling pathway, planar cell polarity pathway / positive regulation of extracellular matrix organization / microspike assembly / B-1 B cell homeostasis / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / mitochondrial depolarization / regulation of cell motility / activated T cell proliferation / positive regulation of establishment of T cell polarity / cellular response to dopamine / positive regulation of blood vessel branching / proline-rich region binding / regulation of Cdc42 protein signal transduction / syntaxin binding / mitogen-activated protein kinase binding / regulation of hematopoietic stem cell differentiation / myoblast proliferation / alpha-beta T cell differentiation / positive regulation of dendrite development / regulation of axon extension / regulation of T cell differentiation / cardiac muscle cell proliferation / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of peptidyl-tyrosine phosphorylation / HDR through Single Strand Annealing (SSA) / negative regulation of cell-cell adhesion / Myogenesis / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / regulation of microtubule polymerization / Fc-gamma receptor signaling pathway involved in phagocytosis / associative learning / vascular endothelial cell response to oscillatory fluid shear stress / Bergmann glial cell differentiation / regulation of endocytosis / neuromuscular process controlling balance / negative regulation of long-term synaptic potentiation / negative regulation of mitotic cell cycle / negative regulation of cellular senescence / negative regulation of BMP signaling pathway / actin monomer binding / canonical NF-kappaB signal transduction / signal transduction in response to DNA damage / positive regulation of focal adhesion assembly / RHO GTPases Activate WASPs and WAVEs / BMP signaling pathway / endothelial cell migration / positive regulation of T cell migration / negative regulation of double-strand break repair via homologous recombination / mismatch repair / negative regulation of endothelial cell apoptotic process / regulation of cell adhesion / peptidyl-tyrosine autophosphorylation / four-way junction DNA binding / cellular response to transforming growth factor beta stimulus / spleen development / positive regulation of stress fiber assembly / ruffle / positive regulation of vasoconstriction / ephrin receptor binding / actin filament polymerization / positive regulation of substrate adhesion-dependent cell spreading / phosphotyrosine residue binding / positive regulation of endothelial cell migration / ERK1 and ERK2 cascade / positive regulation of interleukin-2 production / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / SH2 domain binding / response to endoplasmic reticulum stress / positive regulation of release of sequestered calcium ion into cytosol / thymus development / protein kinase C binding / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / post-embryonic development / integrin-mediated signaling pathway / establishment of localization in cell
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 / SH2 domain superfamily / Src homology 3 domains / 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
AXITINIB / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsJohnson, E. / McTigue, M. / Cronin, C.N.
CitationJournal: Nature / Year: 2015
Title: Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.
Authors: Pemovska, T. / Johnson, E. / Kontro, M. / Repasky, G.A. / Chen, J. / Wells, P. / Cronin, C.N. / McTigue, M. / Kallioniemi, O. / Porkka, K. / Murray, B.W. / Wennerberg, K.
History
DepositionAug 28, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2015Group: Database references
Revision 1.2Mar 18, 2015Group: Database references
Revision 1.3Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.4Dec 27, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.0Aug 7, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / pdbx_distant_solvent_atoms / pdbx_nonpoly_scheme / pdbx_validate_close_contact / pdbx_validate_symm_contact / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _chem_comp_bond.value_order / _pdbx_distant_solvent_atoms.auth_seq_id / _pdbx_distant_solvent_atoms.neighbor_ligand_distance / _pdbx_distant_solvent_atoms.neighbor_macromolecule_distance / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _pdbx_validate_symm_contact.auth_seq_id_1 / _pdbx_validate_symm_contact.auth_seq_id_2 / _struct_site_gen.auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Tyrosine-protein kinase ABL1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,8544
Polymers66,0812
Non-polymers7732
Water5,495305
1
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4272
Polymers33,0411
Non-polymers3861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4272
Polymers33,0411
Non-polymers3861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.626, 111.806, 128.881
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

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


Mass: 33040.723 Da / Num. of mol.: 2 / Fragment: UNP residues 246-512
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-AXI / AXITINIB / N-METHYL-2-(3-((E)-2-PYRIDIN-2-YL-VINYL)-1H-INDAZOL-6-YLSULFANYL)-BENZAMIDE


Mass: 386.470 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H18N4OS / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 305 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.09 Å3/Da / Density % sol: 60.15 %
Crystal growTemperature: 294.15 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 0.1 M Ammonium Chloride 20.0 %w/v PEG 3350 5.0 %v/v Ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 30, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→111.81 Å / Num. all: 41543 / Num. obs: 41543 / % possible obs: 98.5 % / Redundancy: 4.8 % / Rsym value: 0.057 / Net I/σ(I): 15.9
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.489 / Mean I/σ(I) obs: 3 / % possible all: 99.7

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Processing

Software
NameVersionClassification
XDSdata scaling
SCALAdata scaling
PHENIX(phenix.refine: 1.8.2_1295)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→51.286 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2123 2091 5.04 %Random
Rwork0.1731 ---
obs0.1751 41498 97.97 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→51.286 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4195 0 56 305 4556
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074462
X-RAY DIFFRACTIONf_angle_d1.1426038
X-RAY DIFFRACTIONf_dihedral_angle_d16.6791643
X-RAY DIFFRACTIONf_chiral_restr0.08637
X-RAY DIFFRACTIONf_plane_restr0.004763
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.25120.29031160.23682630X-RAY DIFFRACTION99
2.2512-2.30750.27121590.22062603X-RAY DIFFRACTION99
2.3075-2.36990.26541570.2052602X-RAY DIFFRACTION99
2.3699-2.43960.22381530.19972555X-RAY DIFFRACTION98
2.4396-2.51830.2341320.19252642X-RAY DIFFRACTION99
2.5183-2.60830.28071240.18962663X-RAY DIFFRACTION99
2.6083-2.71280.22921290.18442630X-RAY DIFFRACTION99
2.7128-2.83620.24941390.18242638X-RAY DIFFRACTION99
2.8362-2.98570.20881590.18092548X-RAY DIFFRACTION97
2.9857-3.17280.24131300.18112634X-RAY DIFFRACTION99
3.1728-3.41770.21271280.18242649X-RAY DIFFRACTION99
3.4177-3.76160.17421380.15522649X-RAY DIFFRACTION98
3.7616-4.30560.1761360.14762607X-RAY DIFFRACTION96
4.3056-5.42370.18561520.15282627X-RAY DIFFRACTION96
5.4237-51.30010.22231390.1742730X-RAY DIFFRACTION94
Refinement TLS params.Method: refined / Origin x: 14.3513 Å / Origin y: 136.9556 Å / Origin z: 32.223 Å
111213212223313233
T0.22 Å2-0.0056 Å20.0022 Å2-0.2318 Å2-0.0283 Å2--0.2371 Å2
L0.088 °20.2249 °20.2087 °2-0.4577 °20.4685 °2--0.6406 °2
S0.0158 Å °-0.0133 Å °0.0212 Å °-0.0527 Å °-0.0257 Å °0.0079 Å °-0.0798 Å °-0.0165 Å °0.0005 Å °
Refinement TLS groupSelection details: all

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