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- PDB-5mo4: ABL1 kinase (T334I_D382N) in complex with asciminib and nilotinib -

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Basic information

Entry
Database: PDB / ID: 5mo4
TitleABL1 kinase (T334I_D382N) in complex with asciminib and nilotinib
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Kinase / drug / inhibitor
Function / homology
Function and homology information


: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / 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 / transitional one stage B cell differentiation ...: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / 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 / transitional one stage B cell differentiation / activation of protein kinase C activity / nicotinate-nucleotide adenylyltransferase activity / regulation of modification of synaptic structure / positive regulation of microtubule binding / 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 / 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 / negative regulation of protein serine/threonine kinase activity / activated T cell proliferation / cellular response to dopamine / regulation of cell motility / regulation of Cdc42 protein signal transduction / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / regulation of hematopoietic stem cell differentiation / syntaxin binding / alpha-beta T cell differentiation / cardiac muscle cell proliferation / regulation of T cell differentiation / regulation of axon extension / HDR through Single Strand Annealing (SSA) / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cell-cell adhesion / Fc-gamma receptor signaling pathway involved in phagocytosis / Myogenesis / regulation of microtubule polymerization / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / 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 / regulation of endocytosis / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / negative regulation of long-term synaptic potentiation / actin monomer binding / endothelial cell migration / RHO GTPases Activate WASPs and WAVEs / 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 / regulation of cell adhesion / BMP signaling pathway / mismatch repair / negative regulation of endothelial cell apoptotic process / four-way junction DNA binding / peptidyl-tyrosine autophosphorylation / 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 / positive regulation of endothelial cell migration / 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 / regulation of autophagy / neural tube closure / establishment of localization in cell / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / protein kinase C binding
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
asciminib / Nilotinib / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 Å
AuthorsCowan-Jacob, S.W.
CitationJournal: Nature / Year: 2017
Title: The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.
Authors: Wylie, A.A. / Schoepfer, J. / Jahnke, W. / Cowan-Jacob, S.W. / Loo, A. / Furet, P. / Marzinzik, A.L. / Pelle, X. / Donovan, J. / Zhu, W. / Buonamici, S. / Hassan, A.Q. / Lombardo, F. / Iyer, ...Authors: Wylie, A.A. / Schoepfer, J. / Jahnke, W. / Cowan-Jacob, S.W. / Loo, A. / Furet, P. / Marzinzik, A.L. / Pelle, X. / Donovan, J. / Zhu, W. / Buonamici, S. / Hassan, A.Q. / Lombardo, F. / Iyer, V. / Palmer, M. / Berellini, G. / Dodd, S. / Thohan, S. / Bitter, H. / Branford, S. / Ross, D.M. / Hughes, T.P. / Petruzzelli, L. / Vanasse, K.G. / Warmuth, M. / Hofmann, F. / Keen, N.J. / Sellers, W.R.
History
DepositionDec 13, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 5, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 12, 2017Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1633
Polymers56,1831
Non-polymers9792
Water5,531307
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area20120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.280, 124.130, 74.660
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-957-

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: 56183.176 Da / Num. of mol.: 1 / Mutation: T334I D382N
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-NIL / Nilotinib / 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide


Mass: 529.516 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H22F3N7O / Comment: medication*YM
#3: Chemical ChemComp-AY7 / asciminib


Mass: 449.838 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18ClF2N5O3 / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 307 / 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: 2.44 Å3/Da / Density % sol: 49.57 % / Description: flat rods
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Reservoir: 18 % (W/V) PEG 3350, 0.2 M POTASSIUM FORMATE, 0.1 M TRIS PH 7.5 Protein: 35.7 MG/ML 20 MM TRIS PH 8, 200 MM NACL, 2 MM TCEP Protocol: 0.6 UL protein solution plus 0.6 UL reservoir solution

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 4, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.166→59.14 Å / Num. obs: 29197 / % possible obs: 98.5 % / Redundancy: 6.6 % / Biso Wilson estimate: 39.45 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 16.4
Reflection shellResolution: 2.166→2.173 Å / Redundancy: 7 % / Rmerge(I) obs: 0.599 / Mean I/σ(I) obs: 3.4 / % possible all: 98

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION December 6data reduction
SCALAdata scaling
BUSTER2.11.4refinement
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.17→59.14 Å / Cor.coef. Fo:Fc: 0.9422 / Cor.coef. Fo:Fc free: 0.9259 / SU R Cruickshank DPI: 0.206 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.218 / SU Rfree Blow DPI: 0.173 / SU Rfree Cruickshank DPI: 0.17
RfactorNum. reflection% reflectionSelection details
Rfree0.217 1439 4.96 %RANDOM
Rwork0.1818 ---
obs0.1836 29028 98.49 %-
Displacement parametersBiso mean: 36.73 Å2
Baniso -1Baniso -2Baniso -3
1-4.1567 Å20 Å20 Å2
2--2.196 Å20 Å2
3----6.3527 Å2
Refine analyzeLuzzati coordinate error obs: 0.238 Å
Refinement stepCycle: LAST / Resolution: 2.17→59.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3393 0 70 307 3770
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013560HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.054848HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1175SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes77HARMONIC2
X-RAY DIFFRACTIONt_gen_planes520HARMONIC5
X-RAY DIFFRACTIONt_it3560HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion16.4
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion443SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4126SEMIHARMONIC4
LS refinement shellResolution: 2.17→2.25 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.252 131 4.68 %
Rwork0.2272 2668 -
all0.2283 2799 -
obs--98.49 %

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