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- PDB-3kf4: Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors... -

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Basic information

Entry
Database: PDB / ID: 3kf4
TitleStructural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Abl / CML / drug resistance / inhibitor / ATP-binding / Kinase / Nucleotide-binding / Oncogene / Tyrosine-protein kinase
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 / DN4 thymocyte differentiation / RUNX1 regulates transcription of genes involved in differentiation of HSCs ...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 / DN4 thymocyte differentiation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / DNA conformation change / 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 / myoblast proliferation / positive regulation of blood vessel branching / proline-rich region binding / syntaxin binding / circulatory system development / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase 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 / cardiac muscle cell proliferation / 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 / associative learning / B cell proliferation / negative regulation of cellular senescence / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / negative regulation of mitotic cell cycle / signal transduction in response to DNA damage / negative regulation of BMP signaling pathway / positive regulation of focal adhesion assembly / canonical NF-kappaB signal transduction / 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 / positive regulation of mitotic cell cycle / SH2 domain binding / 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-B90 / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsZhou, T.
CitationJournal: Chem.Biol.Drug Des. / Year: 2010
Title: Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.
Authors: Zhou, T. / Commodore, L. / Huang, W.S. / Wang, Y. / Sawyer, T.K. / Shakespeare, W.C. / Clackson, T. / Zhu, X. / Dalgarno, D.C.
History
DepositionOct 27, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Sep 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)67,3714
Polymers66,4842
Non-polymers8872
Water6,215345
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6852
Polymers33,2421
Non-polymers4431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6852
Polymers33,2421
Non-polymers4431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.830, 58.720, 76.170
Angle α, β, γ (deg.)90.000, 118.320, 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: 33241.965 Da / Num. of mol.: 2 / Fragment: residues 115-401
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abl, Abl1, c-Abl / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21DE3
References: UniProt: P00520, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-B90 / N-[4-(dimethylphosphoryl)phenyl]-9-[(E)-2-(5-methyl-1H-indazol-4-yl)ethenyl]-9H-purin-6-amine


Mass: 443.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H22N7OP
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 345 / 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: 2.13 Å3/Da / Density % sol: 42.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.1 M TRIS-HCL, pH 8.0, 30% w/v PEG 4000, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 0.979 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 1, 2007
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: 44725 / Num. obs: 44725 / % possible obs: 99 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.8 % / Rmerge(I) obs: 0.073 / Net I/σ(I): 16.2
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.517 / Mean I/σ(I) obs: 0.073 / Num. unique all: 4278 / % possible all: 96.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement
PDB_EXTRACT3.005data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GQG

2gqg


Resolution: 1.9→50 Å / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.24 2071 4.7 %RANDOM
Rwork0.197 ---
obs-41402 93.7 %-
Displacement parametersBiso max: 70.3 Å2 / Biso mean: 28.066 Å2 / Biso min: 10.66 Å2
Baniso -1Baniso -2Baniso -3
1-0.221 Å20 Å20.06 Å2
2---0.227 Å20 Å2
3---0.006 Å2
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4476 0 64 345 4885
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.4371.5
X-RAY DIFFRACTIONc_scbond_it2.3092
X-RAY DIFFRACTIONc_mcangle_it2.1832
X-RAY DIFFRACTIONc_scangle_it3.3922.5
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 DIFFRACTION5AP24283_A.param
X-RAY DIFFRACTION6AP24283_B_new.param

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