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- PDB-8ssn: Abl kinase in complex with SKI and asciminib -

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Basic information

Entry
Database: PDB / ID: 8ssn
TitleAbl kinase in complex with SKI and asciminib
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Complex / Kinase / double drugging
Function / homology
Function and homology information


positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / 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 ...positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / 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 / DNA conformation change / neuroepithelial cell differentiation / : / B cell proliferation involved in immune response / cerebellum morphogenesis / 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 / activated T cell proliferation / positive regulation of establishment of T cell polarity / cellular response to dopamine / positive regulation of blood vessel branching / proline-rich region binding / regulation of Cdc42 protein signal transduction / syntaxin binding / mitogen-activated protein kinase binding / regulation of hematopoietic stem cell differentiation / myoblast proliferation / alpha-beta T cell differentiation / positive regulation of dendrite development / regulation of axon extension / regulation of T cell differentiation / cardiac muscle cell proliferation / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of peptidyl-tyrosine phosphorylation / HDR through Single Strand Annealing (SSA) / negative regulation of cell-cell adhesion / Myogenesis / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / regulation of microtubule polymerization / Fc-gamma receptor signaling pathway involved in phagocytosis / associative learning / vascular endothelial cell response to oscillatory fluid shear stress / Bergmann glial cell differentiation / regulation of endocytosis / neuromuscular process controlling balance / negative regulation of long-term synaptic potentiation / negative regulation of mitotic cell cycle / negative regulation of cellular senescence / negative regulation of BMP signaling pathway / actin monomer binding / canonical NF-kappaB signal transduction / signal transduction in response to DNA damage / positive regulation of focal adhesion assembly / RHO GTPases Activate WASPs and WAVEs / BMP signaling pathway / endothelial cell migration / positive regulation of T cell migration / negative regulation of double-strand break repair via homologous recombination / mismatch repair / negative regulation of endothelial cell apoptotic process / regulation of cell adhesion / peptidyl-tyrosine autophosphorylation / four-way junction DNA binding / cellular response to transforming growth factor beta stimulus / spleen development / positive regulation of stress fiber assembly / ruffle / positive regulation of vasoconstriction / ephrin receptor binding / actin filament polymerization / positive regulation of substrate adhesion-dependent cell spreading / phosphotyrosine residue binding / positive regulation of endothelial cell migration / ERK1 and ERK2 cascade / positive regulation of interleukin-2 production / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / SH2 domain binding / response to endoplasmic reticulum stress / positive regulation of release of sequestered calcium ion into cytosol / thymus development / protein kinase C binding / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / post-embryonic development / integrin-mediated signaling pathway / 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 / SH2 domain / SHC Adaptor Protein / SH3 Domains / : / SH3 domain / SH2 domain ...F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / SH2 domain / SHC Adaptor Protein / SH3 Domains / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Src homology 3 domains / SH3 type barrels. / 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 / Roll / 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 Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
asciminib / Chem-SKI / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.86 Å
AuthorsLudewig, H. / Kim, C. / Kern, D.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2023
Title: A biophysical framework for double-drugging kinases.
Authors: Kim, C. / Ludewig, H. / Hadzipasic, A. / Kutter, S. / Nguyen, V. / Kern, D.
History
DepositionMay 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 6, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)104,66414
Polymers102,3822
Non-polymers2,28312
Water91951
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,4769
Polymers51,1911
Non-polymers1,2858
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,1885
Polymers51,1911
Non-polymers9974
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.478, 103.213, 107.963
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 2 molecules AB

#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: 51190.750 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P00519, non-specific protein-tyrosine kinase

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Non-polymers , 6 types, 63 molecules

#2: Chemical ChemComp-AY7 / asciminib


Mass: 449.838 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H18ClF2N5O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#3: Chemical ChemComp-SKI / 6,7-dimethoxy-N-(4-phenoxyphenyl)quinazolin-4-amine


Mass: 373.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H19N3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 51 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.52 Å3/Da / Density % sol: 51.21 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 8
Details: Crystals of AblFL in complex with SKI and asciminib were obtained by combining 0.3 ul of 600 uM AblFL + 700 uM SKI + 700 uM asciminib (~32 mg/ml) in 5 percent DMSO with 0.4 ul reservoir of 0. ...Details: Crystals of AblFL in complex with SKI and asciminib were obtained by combining 0.3 ul of 600 uM AblFL + 700 uM SKI + 700 uM asciminib (~32 mg/ml) in 5 percent DMSO with 0.4 ul reservoir of 0.1 M Tris-HCl pH 8 + 1.75 M Ammonium sulfate + 2 percent (v/v) polypropylene glycol 400 (PPG 400). The final stock of complex was concentrated from 1 uM AblFL with ~1.2 uM SKI/asciminib after incubation at 4 degree C for 6 h. Screening around this condition yielded crystals in a transparent diamond-shaped or plate-shaped crystals. Crystals were grown at 18 degree C by sitting drop for a few days. The crystals were transferred to a drop of fresh reservoir containing 20 percent Xylitol with matching concentration of inhibitors in 5 percent DMSO for few seconds for cryo-protection

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 2.0.1 / Wavelength: 1.04054 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 1, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.04054 Å / Relative weight: 1
ReflectionResolution: 2.86→47.83 Å / Num. obs: 24343 / % possible obs: 98.28 % / Redundancy: 2 % / Biso Wilson estimate: 73.79 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.08614 / Net I/σ(I): 4.93
Reflection shellResolution: 2.86→2.967 Å / Rmerge(I) obs: 1.367 / Mean I/σ(I) obs: 0.51 / Num. unique obs: 2372 / CC1/2: 0.31

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.86→47.83 Å / SU ML: 0.5 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 40.92 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.348 1189 4.96 %
Rwork0.2977 --
obs0.3002 23968 98.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.86→47.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6466 0 150 51 6667
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0046773
X-RAY DIFFRACTIONf_angle_d0.7299170
X-RAY DIFFRACTIONf_dihedral_angle_d5.753906
X-RAY DIFFRACTIONf_chiral_restr0.045971
X-RAY DIFFRACTIONf_plane_restr0.0061151
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.86-2.990.42131380.39682601X-RAY DIFFRACTION92
3-3.150.42251460.36062836X-RAY DIFFRACTION100
3.15-3.350.36151400.33762844X-RAY DIFFRACTION100
3.35-3.610.3961350.29442871X-RAY DIFFRACTION100
3.61-3.970.31341810.26172850X-RAY DIFFRACTION100
3.97-4.550.28821470.24412859X-RAY DIFFRACTION99
4.55-5.730.36491500.27612916X-RAY DIFFRACTION99
5.73-47.830.3461520.32593002X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.11591.1619-0.11191.65390.27920.1228-0.28370.48250.5035-0.54140.3539-0.3685-0.2817-0.1843-0.09681.0403-0.1280.01990.0804-0.04120.4193-41.45651.534811.2098
21.5846-0.4744-0.87360.88080.88661.4072-0.0509-0.45120.31150.00820.0210.3679-0.0414-0.04350.01920.8392-0.09190.03790.2009-0.02860.3498-32.1525-1.397524.8009
33.2169-0.0956-0.45420.0370.3993.54220.2925-0.3171-0.3484-0.1399-0.2215-0.65150.08530.133-0.09550.67180.0275-0.01430.2189-0.01320.453-19.6099-10.3321.5287
40.79860.29580.05672.1202-1.24181.9135-0.0043-0.6347-0.23890.4015-0.0141-0.245-0.2668-0.14070.13650.5793-0.0584-0.08430.64360.37580.3333-14.9056-16.625937.6978
50.58490.54090.2251.855-0.94532.2066-0.0999-0.0736-0.26520.0062-0.06950.3372-0.50990.21260.04490.9802-0.04260.08650.359-0.07250.848339.1396-22.422816.0287
64.17721.22920.44574.4116-0.64165.9315-0.1726-0.50440.36750.5169-0.3802-0.0178-0.10330.33210.47560.7771-0.05810.00830.49970.10030.811842.821-27.501736.5235
73.17041.04010.31192.1890.72234.010.21190.4646-0.142-0.3574-0.0931-0.0121-0.3371-0.4846-0.11330.80230.22450.06420.4378-0.09330.606621.0903-10.783716.977
82.684-1.42390.44965.68981.47092.75530.1387-0.7140.8460.0757-0.30350.08420.00320.0350.07820.7513-0.17220.07350.7595-0.36141.004415.8351-4.462735.7207
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 82 through 152 )
2X-RAY DIFFRACTION2chain 'A' and (resid 153 through 311 )
3X-RAY DIFFRACTION3chain 'A' and (resid 312 through 403 )
4X-RAY DIFFRACTION4chain 'A' and (resid 404 through 526 )
5X-RAY DIFFRACTION5chain 'B' and (resid 82 through 172 )
6X-RAY DIFFRACTION6chain 'B' and (resid 173 through 241 )
7X-RAY DIFFRACTION7chain 'B' and (resid 242 through 375 )
8X-RAY DIFFRACTION8chain 'B' and (resid 376 through 525 )

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