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- PDB-7n9g: Crystal structure of the Abl 1b Kinase domain in complex with Das... -

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Basic information

Entry
Database: PDB / ID: 7n9g
TitleCrystal structure of the Abl 1b Kinase domain in complex with Dasatinib and Imatinib
ComponentsTyrosine-protein kinase ABL1
KeywordsCELL CYCLE / Abl kinase / kinase allosteric regulation / drug resistance
Function / homology
Function and homology information


: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine / transitional one stage B cell differentiation ...: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine / transitional one stage B cell differentiation / activation of protein kinase C activity / nicotinate-nucleotide adenylyltransferase activity / regulation of modification of synaptic structure / positive regulation of microtubule binding / 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 / cerebellum morphogenesis / positive regulation of blood vessel branching / B-1 B cell homeostasis / mitochondrial depolarization / negative regulation of ubiquitin-protein transferase activity / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / negative regulation of protein serine/threonine kinase activity / activated T cell proliferation / cellular response to dopamine / regulation of cell motility / regulation of Cdc42 protein signal transduction / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / regulation of hematopoietic stem cell differentiation / syntaxin binding / alpha-beta T cell differentiation / cardiac muscle cell proliferation / regulation of T cell differentiation / regulation of axon extension / HDR through Single Strand Annealing (SSA) / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cell-cell adhesion / Fc-gamma receptor signaling pathway involved in phagocytosis / Myogenesis / regulation of microtubule polymerization / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / 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 / regulation of endocytosis / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / negative regulation of long-term synaptic potentiation / actin monomer binding / endothelial cell migration / RHO GTPases Activate WASPs and WAVEs / 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 / regulation of cell adhesion / BMP signaling pathway / mismatch repair / negative regulation of endothelial cell apoptotic process / four-way junction DNA binding / peptidyl-tyrosine autophosphorylation / 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 / positive regulation of endothelial cell migration / 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 / regulation of autophagy / neural tube closure / establishment of localization in cell / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / protein kinase C binding
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-1N1 / PHOSPHATE ION / Chem-STI / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsMiller, D.J. / Xie, T.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Office of the Director5R35GM122462-05 United States
CitationJournal: J.Mol.Biol. / Year: 2022
Title: Imatinib can act as an Allosteric Activator of Abl Kinase.
Authors: Xie, T. / Saleh, T. / Rossi, P. / Miller, D. / Kalodimos, C.G.
History
DepositionJun 17, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 27, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)97,51610
Polymers94,4763
Non-polymers3,0407
Water3,711206
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5694
Polymers31,4921
Non-polymers1,0773
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4743
Polymers31,4921
Non-polymers9822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4743
Polymers31,4921
Non-polymers9822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.933, 166.879, 186.817
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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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: 31492.072 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Production host: Escherichia coli (E. coli)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: 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.: 3 / Source method: obtained synthetically / Formula: C29H31N7O / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#3: Chemical ChemComp-1N1 / N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE / Dasatinib


Mass: 488.006 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H26ClN7O2S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 206 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.88 Å3/Da / Density % sol: 57.36 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / Details: Ammonium dihydrogen phosphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Mar 31, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→46.7 Å / Num. obs: 55951 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 8.6 % / CC1/2: 0.999 / Rpim(I) all: 0.03 / Rsym value: 0.083 / Net I/σ(I): 15.1
Reflection shellResolution: 2.2→2.26 Å / Redundancy: 8.7 % / Num. unique obs: 4480 / CC1/2: 0.762 / Rsym value: 1.184 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GQG

2gqg


Resolution: 2.2→46.7 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.939 / SU B: 7.206 / SU ML: 0.175 / Cross valid method: THROUGHOUT / ESU R: 0.231 / ESU R Free: 0.193
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2511 2704 4.834 %
Rwork0.2174 53232 -
all0.219 --
obs-55936 99.759 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 52.067 Å2
Baniso -1Baniso -2Baniso -3
1-3.585 Å2-0 Å2-0 Å2
2---1.887 Å2-0 Å2
3----1.698 Å2
Refinement stepCycle: LAST / Resolution: 2.2→46.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5886 0 215 206 6307
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0136264
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175577
X-RAY DIFFRACTIONr_angle_refined_deg1.2891.6448506
X-RAY DIFFRACTIONr_angle_other_deg1.2441.5712872
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7125736
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.25522.91299
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.4115978
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.5061527
X-RAY DIFFRACTIONr_chiral_restr0.0560.2776
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026973
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021361
X-RAY DIFFRACTIONr_nbd_refined0.1960.21178
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1760.24971
X-RAY DIFFRACTIONr_nbtor_refined0.170.23066
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0810.22464
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1390.2196
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1590.210
X-RAY DIFFRACTIONr_nbd_other0.1950.235
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1450.28
X-RAY DIFFRACTIONr_mcbond_it3.175.6482980
X-RAY DIFFRACTIONr_mcbond_other3.175.6472978
X-RAY DIFFRACTIONr_mcangle_it4.7418.4463702
X-RAY DIFFRACTIONr_mcangle_other4.7418.4473703
X-RAY DIFFRACTIONr_scbond_it3.8455.8343282
X-RAY DIFFRACTIONr_scbond_other3.8435.8363279
X-RAY DIFFRACTIONr_scangle_it5.9098.6274803
X-RAY DIFFRACTIONr_scangle_other5.9088.6314798
X-RAY DIFFRACTIONr_lrange_it7.47462.8317051
X-RAY DIFFRACTIONr_lrange_other7.47362.8117035
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.2550.311940.3063811X-RAY DIFFRACTION98.2099
2.255-2.3160.3152160.33794X-RAY DIFFRACTION99.9751
2.316-2.3840.3081740.2623684X-RAY DIFFRACTION99.9223
2.384-2.4570.3011950.2543588X-RAY DIFFRACTION99.9208
2.457-2.5370.3031820.2483463X-RAY DIFFRACTION100
2.537-2.6260.2931750.2493387X-RAY DIFFRACTION100
2.626-2.7260.2641530.2273285X-RAY DIFFRACTION99.9419
2.726-2.8370.2861630.2123125X-RAY DIFFRACTION100
2.837-2.9630.2581580.2143025X-RAY DIFFRACTION100
2.963-3.1070.31460.222867X-RAY DIFFRACTION99.8674
3.107-3.2750.2611410.2072758X-RAY DIFFRACTION99.9311
3.275-3.4740.2391170.2122636X-RAY DIFFRACTION99.8549
3.474-3.7140.2461300.212459X-RAY DIFFRACTION99.8457
3.714-4.0110.2141070.1982264X-RAY DIFFRACTION99.6637
4.011-4.3930.209920.1782160X-RAY DIFFRACTION99.8227
4.393-4.9110.206920.1841923X-RAY DIFFRACTION99.9008
4.911-5.6690.273990.2121709X-RAY DIFFRACTION100
5.669-6.940.289740.241462X-RAY DIFFRACTION99.9349
6.94-9.7990.204570.1921157X-RAY DIFFRACTION100

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