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- PDB-3qrj: The crystal structure of human abl1 kinase domain T315I mutant in... -

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Basic information

Entry
Database: PDB / ID: 3qrj
TitleThe crystal structure of human abl1 kinase domain T315I mutant in complex with DCC-2036
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / ABL1 / KINASE / KINASE DOMAIN / T315I / gatekeeper mutation / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of phospholipase C activity / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / transitional one stage B cell differentiation / 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 ...negative regulation of phospholipase C activity / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / transitional one stage B cell differentiation / 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 / activation of protein kinase C activity / nicotinate-nucleotide adenylyltransferase activity / regulation of modification of synaptic structure / positive regulation of extracellular matrix organization / positive regulation of microtubule binding / delta-catenin binding / B cell proliferation involved in immune response / 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 / regulation of Cdc42 protein signal transduction / negative regulation of protein serine/threonine kinase activity / activated T cell proliferation / cellular response to dopamine / regulation of cell motility / regulation of axon extension / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / alpha-beta T cell differentiation / regulation of hematopoietic stem cell differentiation / syntaxin binding / cardiac muscle cell proliferation / HDR through Single Strand Annealing (SSA) / regulation of T cell differentiation / negative regulation of double-strand break repair via homologous recombination / positive regulation of cell migration involved in sprouting angiogenesis / Fc-gamma receptor signaling pathway involved in phagocytosis / negative regulation of cell-cell adhesion / Myogenesis / regulation of microtubule polymerization / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of focal adhesion assembly / negative regulation of cellular senescence / negative regulation of long-term synaptic potentiation / Bergmann glial cell differentiation / associative learning / neuromuscular process controlling balance / regulation of endocytosis / actin monomer binding / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / mismatch repair / endothelial cell migration / RHO GTPases Activate WASPs and WAVEs / positive regulation of T cell migration / canonical NF-kappaB signal transduction / BMP signaling pathway / negative regulation of endothelial cell apoptotic process / regulation of cell adhesion / positive regulation of substrate adhesion-dependent cell spreading / four-way junction DNA binding / signal transduction in response to DNA damage / peptidyl-tyrosine autophosphorylation / positive regulation of vasoconstriction / spleen development / positive regulation of stress fiber assembly / ruffle / ERK1 and ERK2 cascade / cellular response to transforming growth factor beta stimulus / positive regulation of establishment of T cell polarity / positive regulation of interleukin-2 production / actin filament polymerization / SH2 domain binding / response to endoplasmic reticulum stress / phosphotyrosine residue binding / ephrin receptor binding / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / post-embryonic development / protein kinase C binding / positive regulation of release of sequestered calcium ion into cytosol / positive regulation of endothelial cell migration / thymus development / regulation of autophagy / neural tube closure / integrin-mediated signaling pathway / establishment of localization in cell / 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 / 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
Chem-919 / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsChan, W.W. / Wise, S.C. / Kaufman, M.D. / Ahn, Y.M. / Ensinger, C.L. / Haack, T. / Hood, M.M. / Jones, J. / Lord, J.W. / Lu, W.P. ...Chan, W.W. / Wise, S.C. / Kaufman, M.D. / Ahn, Y.M. / Ensinger, C.L. / Haack, T. / Hood, M.M. / Jones, J. / Lord, J.W. / Lu, W.P. / Miller, D. / Patt, W.C. / Smith, B.D. / Petillo, P.A. / Rutkoski, T.J. / Telikepalli, H. / Vogeti, L. / Yao, T. / Chun, L. / Clark, R. / Evangelista, P. / Gavrilescu, L.C. / Lazarides, K. / Zaleskas, V.M. / Stewart, L.J. / Van Etten, R.A. / Flynn, D.L.
CitationJournal: Cancer Cell / Year: 2011
Title: Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036.
Authors: Chan, W.W. / Wise, S.C. / Kaufman, M.D. / Ahn, Y.M. / Ensinger, C.L. / Haack, T. / Hood, M.M. / Jones, J. / Lord, J.W. / Lu, W.P. / Miller, D. / Patt, W.C. / Smith, B.D. / Petillo, P.A. / ...Authors: Chan, W.W. / Wise, S.C. / Kaufman, M.D. / Ahn, Y.M. / Ensinger, C.L. / Haack, T. / Hood, M.M. / Jones, J. / Lord, J.W. / Lu, W.P. / Miller, D. / Patt, W.C. / Smith, B.D. / Petillo, P.A. / Rutkoski, T.J. / Telikepalli, H. / Vogeti, L. / Yao, T. / Chun, L. / Clark, R. / Evangelista, P. / Gavrilescu, L.C. / Lazarides, K. / Zaleskas, V.M. / Stewart, L.J. / Van Etten, R.A. / Flynn, D.L.
History
DepositionFeb 18, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 1, 2011Provider: 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)65,3534
Polymers64,2462
Non-polymers1,1072
Water4,378243
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6762
Polymers32,1231
Non-polymers5541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6762
Polymers32,1231
Non-polymers5541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: Tyrosine-protein kinase ABL1
hetero molecules

B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,3534
Polymers64,2462
Non-polymers1,1072
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_545x,y-1,z1
Buried area1550 Å2
ΔGint-11 kcal/mol
Surface area23410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.261, 59.435, 76.285
Angle α, β, γ (deg.)90.00, 109.55, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 32122.789 Da / Num. of mol.: 2 / Fragment: Kinase domain, UNP residues 229-499 / Mutation: T315I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-919 / 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide / DCC-2036


Mass: 553.587 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H28FN7O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 243 / 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: 1.84 Å3/Da / Density % sol: 33.06 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 7.1
Details: 29% PEG 3350, 100MM BISTRIS PH 7.1, VAPOR DIFFUSION, SITTING DROP, TEMPERATURE 290K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 3, 2006
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: 1.82→20 Å / Num. all: 43355 / Num. obs: 41838 / % possible obs: 96.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 20 Å2 / Rsym value: 0.087 / Net I/σ(I): 16.1
Reflection shellResolution: 1.82→1.89 Å / Rmerge(I) obs: 0.408 / Mean I/σ(I) obs: 2.2 / % possible all: 80.4

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Processing

Software
NameVersionClassification
BOSdata collection
MOLREPphasing
REFMAC5.5.0088refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Abl kinase

Resolution: 1.82→19.59 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.876 / SU B: 4.447 / SU ML: 0.139 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.184 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE
RfactorNum. reflection% reflectionSelection details
Rfree0.286 2035 5 %RANDOM
Rwork0.229 ---
all0.232 43355 --
obs0.232 40360 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 16.58 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å20 Å20.02 Å2
2--0.11 Å20 Å2
3----0.04 Å2
Refinement stepCycle: LAST / Resolution: 1.82→19.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4128 0 82 243 4453
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0224373
X-RAY DIFFRACTIONr_bond_other_d0.0010.022898
X-RAY DIFFRACTIONr_angle_refined_deg1.7241.9775955
X-RAY DIFFRACTIONr_angle_other_deg0.97837045
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0225534
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.15723.641184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.62615712
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1691521
X-RAY DIFFRACTIONr_chiral_restr0.0920.2635
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214867
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02940
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8641.52628
X-RAY DIFFRACTIONr_mcbond_other0.2331.51060
X-RAY DIFFRACTIONr_mcangle_it1.46324212
X-RAY DIFFRACTIONr_scbond_it2.24831745
X-RAY DIFFRACTIONr_scangle_it3.3514.51737
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.82→1.87 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.333 105 -
Rwork0.318 2268 -
obs--77.47 %

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