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- PDB-3oy3: Crystal structure of ABL T315I mutant kinase domain bound with a ... -

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Basic information

Entry
Database: PDB / ID: 3oy3
TitleCrystal structure of ABL T315I mutant kinase domain bound with a DFG-out inhibitor AP24589
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Protein-inhibitor complex / Protein kinase two-domain fold / phosphotransferase / ATP binding / phosphorylation / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / 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 / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / response to epinephrine / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / delta-catenin binding / transitional one stage B cell differentiation / regulation of cellular senescence / regulation of postsynaptic specialization assembly / regulation of modification of synaptic structure / cerebellum morphogenesis / neuroepithelial cell differentiation / B cell proliferation involved in immune response / Regulation of actin dynamics for phagocytic cup formation / 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 / regulation of extracellular matrix organization / neuropilin binding / bubble DNA binding / Myogenesis / positive regulation of establishment of T cell polarity / activated T cell proliferation / positive regulation of blood vessel branching / proline-rich region binding / circulatory system development / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / syntaxin binding / alpha-beta T cell differentiation / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of dendrite development / regulation of axon extension / regulation of T cell differentiation / positive regulation of peptidyl-tyrosine phosphorylation / negative regulation of cell-cell adhesion / positive regulation of osteoblast proliferation / platelet-derived growth factor receptor-beta signaling pathway / cell leading edge / platelet-derived growth factor receptor signaling pathway / regulation of microtubule polymerization / Bergmann glial cell differentiation / B cell proliferation / myoblast proliferation / associative learning / negative regulation of long-term synaptic potentiation / negative regulation of cellular senescence / negative regulation of mitotic cell cycle / neuromuscular process controlling balance / signal transduction in response to DNA damage / negative regulation of BMP signaling pathway / positive regulation of focal adhesion assembly / canonical NF-kappaB signal transduction / cardiac muscle cell proliferation / BMP signaling pathway / phagocytosis / ephrin receptor signaling pathway / positive regulation of T cell migration / endothelial cell migration / negative regulation of double-strand break repair via homologous recombination / cellular response to transforming growth factor beta stimulus / negative regulation of endothelial cell apoptotic process / positive regulation of vasoconstriction / four-way junction DNA binding / spleen development / positive regulation of stress fiber assembly / ephrin receptor binding / ruffle / ERK1 and ERK2 cascade / actin filament polymerization / phosphotyrosine residue binding / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of interleukin-2 production / substrate adhesion-dependent cell spreading / SH2 domain binding / positive regulation of mitotic cell cycle / protein kinase C binding / response to endoplasmic reticulum stress / positive regulation of release of sequestered calcium ion into cytosol / thymus development / integrin-mediated signaling pathway / post-embryonic development / B cell receptor signaling pathway / regulation of actin cytoskeleton organization / neural tube closure / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / enzyme activator activity / 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 / 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
Chem-XY3 / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsZhou, T. / Commodore, L. / Huang, W.S. / Wang, Y. / Thomas, M. / Keats, J. / Xu, Q. / Rivera, V. / Shakespeare, W.C. / Clackson, T. ...Zhou, T. / Commodore, L. / Huang, W.S. / Wang, Y. / Thomas, M. / Keats, J. / Xu, Q. / Rivera, V. / Shakespeare, W.C. / Clackson, T. / Dalgarno, D.C. / Zhu, X.
CitationJournal: Chem.Biol.Drug Des. / Year: 2011
Title: Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance.
Authors: Zhou, T. / Commodore, L. / Huang, W.S. / Wang, Y. / Thomas, M. / Keats, J. / Xu, Q. / Rivera, V.M. / Shakespeare, W.C. / Clackson, T. / Dalgarno, D.C. / Zhu, X.
History
DepositionSep 22, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 15, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)66,7564
Polymers65,6192
Non-polymers1,1372
Water7,044391
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3782
Polymers32,8091
Non-polymers5691
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3782
Polymers32,8091
Non-polymers5691
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.471, 59.988, 89.439
Angle α, β, γ (deg.)90.000, 97.970, 90.000
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: 32809.492 Da / Num. of mol.: 2 / Fragment: UNP residues 229-511 / Mutation: T315I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abl1, Abl / Production host: Escherichia coli (E. coli)
References: UniProt: P00520, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-XY3 / 5-[(5-{[4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-3-(trifluoromethyl)phenyl]carbamoyl}-2-methylphenyl)ethynyl]-1-methyl-1H-imidazole-2-carboxamide


Mass: 568.590 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H31F3N6O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 391 / 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: 2.69 Å3/Da / Density % sol: 54.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 30% w/v polyethylene glycol, 0.2 M sodium acetate, 0.1 M Trs-HCl, pH 8.5, 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
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Oct 17, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. all: 51089 / Num. obs: 46310 / % possible obs: 90.6 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1
Reflection shellResolution: 1.95→2.02 Å / % possible all: 98.2

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Processing

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

1iep


Resolution: 1.95→50 Å / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2657 2338 4.6 %Random
Rwork0.2201 ---
all-51089 --
obs-46310 90.6 %-
Displacement parametersBiso max: 73.31 Å2 / Biso mean: 27.4662 Å2 / Biso min: 4.86 Å2
Baniso -1Baniso -2Baniso -3
1--0.005 Å20 Å20.091 Å2
2---0.224 Å20 Å2
3---0.229 Å2
Refinement stepCycle: LAST / Resolution: 1.95→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4600 0 82 391 5073
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.5131.5
X-RAY DIFFRACTIONc_scbond_it2.2492
X-RAY DIFFRACTIONc_mcangle_it2.3252
X-RAY DIFFRACTIONc_scangle_it3.1782.5
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_589.param

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