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- PDB-6hd4: ABL1 IN COMPLEX WITH COMPOUND 7 AND IMATINIB (STI-571) -

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Basic information

Entry
Database: PDB / ID: 6hd4
TitleABL1 IN COMPLEX WITH COMPOUND 7 AND IMATINIB (STI-571)
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / PHOSPHOTRANSFERASE / 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-FYW / Chem-STI / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.03 Å
AuthorsCowan-Jacob, S.W.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1.
Authors: Schoepfer, J. / Jahnke, W. / Berellini, G. / Buonamici, S. / Cotesta, S. / Cowan-Jacob, S.W. / Dodd, S. / Drueckes, P. / Fabbro, D. / Gabriel, T. / Groell, J.M. / Grotzfeld, R.M. / Hassan, A. ...Authors: Schoepfer, J. / Jahnke, W. / Berellini, G. / Buonamici, S. / Cotesta, S. / Cowan-Jacob, S.W. / Dodd, S. / Drueckes, P. / Fabbro, D. / Gabriel, T. / Groell, J.M. / Grotzfeld, R.M. / Hassan, A.Q. / Henry, C. / Iyer, V. / Jones, D. / Lombardo, F. / Loo, A. / Manley, P.W. / Pelle, X. / Rummel, G. / Salem, B. / Warmuth, M. / Wylie, A.A. / Zoller, T. / Marzinzik, A.L. / Furet, P.
History
DepositionAug 17, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 24, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)69,4938
Polymers67,4872
Non-polymers2,0066
Water6,918384
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8105
Polymers33,7441
Non-polymers1,0674
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6833
Polymers33,7441
Non-polymers9392
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.160, 65.025, 66.086
Angle α, β, γ (deg.)73.00, 80.52, 84.88
Int Tables number1
Space group name H-MP1

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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: 33743.523 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Details: The electron density for the region A294-A297 is poor and a good fit could not be found
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abl1, Abl / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P00520, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 390 molecules

#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-FYW / 6-[(3~{R})-3-oxidanylpyrrolidin-1-yl]-5-pyrimidin-5-yl-~{N}-[4-(trifluoromethyloxy)phenyl]pyridine-3-carboxamide


Mass: 445.395 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18F3N5O3
#5: Chemical ChemComp-STI / 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE / STI-571 / IMATINIB


Mass: 493.603 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H31N7O / Comment: medication, inhibitor*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 384 / 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: 2.53 Å3/Da / Density % sol: 51.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 20.0 % PEG 4000, 0.2 M MGCL2, 0.1 M MES PH 5.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 7, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.03→62.12 Å / Num. obs: 39687 / % possible obs: 92.7 % / Observed criterion σ(I): 0 / Redundancy: 1.8 % / Rmerge(I) obs: 0.031 / Net I/σ(I): 15.82
Reflection shellResolution: 2.03→2.09 Å / Redundancy: 1.81 % / Rmerge(I) obs: 0.187 / Mean I/σ(I) obs: 4.08 / Num. unique all: 3316 / % possible all: 92.8

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Processing

Software
NameVersionClassification
BUSTER2.9.3refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1OPJ

1opj


Resolution: 2.03→40.4 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflectionSelection details
Rfree0.2228 1985 5 %Random
Rwork0.1811 ---
obs0.1832 39685 92.82 %-
Displacement parametersBiso mean: 36.77 Å2
Baniso -1Baniso -2Baniso -3
1--0.5017 Å2-1.2921 Å2-3.2388 Å2
2--3.6794 Å2-0.6722 Å2
3----3.1778 Å2
Refine analyzeLuzzati coordinate error obs: 0.223 Å
Refinement stepCycle: LAST / Resolution: 2.03→40.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4624 0 145 384 5153
LS refinement shellResolution: 2.03→2.08 Å
RfactorNum. reflection% reflection
Rfree0.26 147 5.02 %
Rwork0.2043 2782 -
obs--92.82 %

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