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- PDB-5hu9: Crystal structure of ABL1 in complex with CHMFL-074 -

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Basic information

Entry
Database: PDB / ID: 5hu9
TitleCrystal structure of ABL1 in complex with CHMFL-074
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Abl / BCR-Abl / CHMFL-074 / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


: / positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process ...: / positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / delta-catenin binding / Role of ABL in ROBO-SLIT signaling / transitional one stage B cell differentiation / regulation of postsynaptic specialization assembly / regulation of modification of synaptic structure / nicotinate-nucleotide adenylyltransferase activity / cerebellum morphogenesis / neuroepithelial cell differentiation / B cell proliferation involved in immune response / 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 / neuropilin binding / bubble DNA binding / mitochondrial depolarization / regulation of cell motility / positive regulation of establishment of T cell polarity / activated T cell proliferation / cellular response to dopamine / positive regulation of blood vessel branching / proline-rich region binding / negative regulation of mitotic cell cycle / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / syntaxin binding / regulation of hematopoietic stem cell differentiation / alpha-beta T cell differentiation / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of dendrite development / peptidyl-tyrosine autophosphorylation / regulation of axon extension / regulation of T cell differentiation / positive regulation of peptidyl-tyrosine phosphorylation / negative regulation of cell-cell adhesion / HDR through Single Strand Annealing (SSA) / neuromuscular process controlling balance / positive regulation of osteoblast proliferation / Myogenesis / positive regulation of vasoconstriction / platelet-derived growth factor receptor-beta signaling pathway / RUNX2 regulates osteoblast differentiation / Fc-gamma receptor signaling pathway involved in phagocytosis / Bergmann glial cell differentiation / vascular endothelial cell response to oscillatory fluid shear stress / regulation of endocytosis / regulation of microtubule polymerization / myoblast proliferation / associative learning / negative regulation of long-term synaptic potentiation / negative regulation of cellular senescence / actin monomer binding / signal transduction in response to DNA damage / negative regulation of BMP signaling pathway / positive regulation of focal adhesion assembly / RHO GTPases Activate WASPs and WAVEs / canonical NF-kappaB signal transduction / cardiac muscle cell proliferation / BMP signaling pathway / ephrin receptor signaling pathway / positive regulation of T cell migration / endothelial cell migration / negative regulation of double-strand break repair via homologous recombination / negative regulation of endothelial cell apoptotic process / cellular response to transforming growth factor beta stimulus / mismatch repair / regulation of cell adhesion / four-way junction DNA binding / spleen development / ephrin receptor binding / positive regulation of stress fiber assembly / 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 / positive regulation of endothelial cell migration / 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 / peptidyl-tyrosine phosphorylation / thymus development / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / integrin-mediated signaling pathway / post-embryonic development
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-66K / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.529 Å
AuthorsKong, L.L. / Yun, C.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Science Foundation of China31270769 China
National Basic Research Program of China2012CB917202 China
CitationJournal: Oncotarget / Year: 2016
Title: Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)
Authors: Liu, F. / Wang, B. / Wang, Q. / Qi, Z. / Chen, C. / Kong, L.L. / Chen, J.Y. / Liu, X. / Wang, A. / Hu, C. / Wang, W. / Wang, H. / Wu, F. / Ruan, Y. / Qi, S. / Liu, J. / Zou, F. / Hu, Z. / ...Authors: Liu, F. / Wang, B. / Wang, Q. / Qi, Z. / Chen, C. / Kong, L.L. / Chen, J.Y. / Liu, X. / Wang, A. / Hu, C. / Wang, W. / Wang, H. / Wu, F. / Ruan, Y. / Qi, S. / Liu, J. / Zou, F. / Hu, Z. / Wang, W. / Wang, L. / Zhang, S. / Yun, C.H. / Zhai, Z. / Liu, J. / Liu, Q.
History
DepositionJan 27, 2016Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jul 13, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Database references
Revision 1.2Nov 8, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,95416
Polymers31,9831
Non-polymers1,97215
Water6,575365
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-10 kcal/mol
Surface area13660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.852, 108.435, 146.295
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-852-

HOH

21A-998-

HOH

31A-1045-

HOH

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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: 31982.609 Da / Num. of mol.: 1 / Fragment: UNP residues 229-500
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-66K / 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]oxy}phenyl)-3-(trifluoromethyl)benzamide


Mass: 595.655 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H36F3N5O3
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 365 / 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: 2.35 Å3/Da / Density % sol: 47.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1M Potassium thiocyanate, 28% PEG2000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.529→50 Å / Num. obs: 44923 / % possible obs: 97.7 % / Redundancy: 12 % / Rmerge(I) obs: 0.028 / Net I/σ(I): 27.1
Reflection shellResolution: 1.529→1.56 Å

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-3000data processing
PHASERphasing
Cootmodel building
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3CS9

3cs9


Resolution: 1.529→43.557 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1961 2268 5.06 %
Rwork0.1857 --
obs0.1862 44782 97.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.529→43.557 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2165 0 135 365 2665
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0642450
X-RAY DIFFRACTIONf_angle_d1.683315
X-RAY DIFFRACTIONf_dihedral_angle_d22.393918
X-RAY DIFFRACTIONf_chiral_restr0.174342
X-RAY DIFFRACTIONf_plane_restr0.011409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5292-1.56240.28691460.2672258X-RAY DIFFRACTION85
1.5624-1.59880.29531360.2542485X-RAY DIFFRACTION91
1.5988-1.63880.24891280.2482507X-RAY DIFFRACTION92
1.6388-1.68310.27411190.24192572X-RAY DIFFRACTION96
1.6831-1.73260.24931460.23932599X-RAY DIFFRACTION95
1.7326-1.78850.27861390.22562659X-RAY DIFFRACTION98
1.7885-1.85250.24861500.22362645X-RAY DIFFRACTION99
1.8525-1.92660.24611380.21462684X-RAY DIFFRACTION99
1.9266-2.01430.2241330.2082720X-RAY DIFFRACTION100
2.0143-2.12050.21741540.19592718X-RAY DIFFRACTION100
2.1205-2.25340.20211330.20042718X-RAY DIFFRACTION100
2.2534-2.42730.19681430.19272732X-RAY DIFFRACTION100
2.4273-2.67160.20091290.19392758X-RAY DIFFRACTION100
2.6716-3.05810.17671640.19422757X-RAY DIFFRACTION100
3.0581-3.85250.15751370.15322821X-RAY DIFFRACTION100
3.8525-43.57480.17381730.15562881X-RAY DIFFRACTION99

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