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- PDB-3ik3: AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Po... -

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Entry
Database: PDB / ID: 3ik3
TitleAP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance
ComponentsProto-oncogene tyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Bcr-Abl / CML / T315I / inhibitor / mutation / drug resistance / Alternative splicing / ATP-binding / Cell adhesion / Chromosomal rearrangement / Cytoplasm / Cytoskeleton / Kinase / Lipoprotein / Magnesium / Manganese / Metal-binding / Myristate / Nucleotide-binding / Nucleus / Phosphoprotein / Proto-oncogene / SH2 domain / SH3 domain
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
Chem-0LI / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsZhou, T.
CitationJournal: Cancer Cell / Year: 2009
Title: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
Authors: O'Hare, T. / Shakespeare, W.C. / Zhu, X. / Eide, C.A. / Rivera, V.M. / Wang, F. / Adrian, L.T. / Zhou, T. / Huang, W.S. / Xu, Q. / Metcalf, C.A. / Tyner, J.W. / Loriaux, M.M. / Corbin, A.S. ...Authors: O'Hare, T. / Shakespeare, W.C. / Zhu, X. / Eide, C.A. / Rivera, V.M. / Wang, F. / Adrian, L.T. / Zhou, T. / Huang, W.S. / Xu, Q. / Metcalf, C.A. / Tyner, J.W. / Loriaux, M.M. / Corbin, A.S. / Wardwell, S. / Ning, Y. / Keats, J.A. / Wang, Y. / Sundaramoorthi, R. / Thomas, M. / Zhou, D. / Snodgrass, J. / Commodore, L. / Sawyer, T.K. / Dalgarno, D.C. / Deininger, M.W. / Druker, B.J. / Clackson, T.
History
DepositionAug 5, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 3, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_entity_nonpoly / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
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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)67,5734
Polymers66,5082
Non-polymers1,0652
Water8,269459
1
A: Proto-oncogene tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7872
Polymers33,2541
Non-polymers5331
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)33,7872
Polymers33,2541
Non-polymers5331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.907, 131.453, 60.200
Angle α, β, γ (deg.)90.000, 92.870, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 33254.020 Da / Num. of mol.: 2 / Mutation: T315I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abl1, Abl / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21DE3
References: UniProt: P00520, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0LI / 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide / Ponatinib


Mass: 532.559 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27F3N6O / Comment: medication*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 459 / 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: 2.61 Å3/Da / Density % sol: 52.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.1 M Tris-HCl (pH 8.5), 30% w/v polyethylene glycol 4000, and 0.2 M sodium acetate, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.979 Å
DetectorDetector: CCD / Date: Aug 25, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 53537 / Num. obs: 48583 / Redundancy: 4 % / Rmerge(I) obs: 0.081 / Net I/σ(I): 16.1
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.289 / Mean I/σ(I) obs: 3.8 / Num. unique all: 4324 / % possible all: 81.8

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT3.005data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1IEP

1iep


Resolution: 1.9→50 Å / Occupancy max: 1 / Occupancy min: 1 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.258 2443 4.6 %Random
Rwork0.216 ---
all-52977 --
obs-48583 90.7 %-
Displacement parametersBiso max: 57.52 Å2 / Biso mean: 19.278 Å2 / Biso min: 2.6 Å2
Baniso -1Baniso -2Baniso -3
1-0.081 Å20 Å2-0.053 Å2
2---0.057 Å20 Å2
3----0.024 Å2
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4600 0 78 459 5137
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.4491.5
X-RAY DIFFRACTIONc_scbond_it2.2222
X-RAY DIFFRACTIONc_mcangle_it2.0592
X-RAY DIFFRACTIONc_scangle_it3.052.5
LS refinement shellResolution: 1.9→1.97 Å /
Num. reflection% reflection
obs4324 81.8 %
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2dna-rna_rep.param
X-RAY DIFFRACTION3water_rep.param
X-RAY DIFFRACTION4ion.param
X-RAY DIFFRACTION5ligand.param

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