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- PDB-6hd6: ABL1 IN COMPLEX WITH COMPOUND6 AND IMATINIB (STI-571) -

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Basic information

Entry
Database: PDB / ID: 6hd6
TitleABL1 IN COMPLEX WITH COMPOUND6 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 / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / circulatory system development / transitional one stage B cell differentiation / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process ...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 / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / circulatory system development / transitional one stage B cell differentiation / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / response to epinephrine / regulation of cellular senescence / regulation of modification of synaptic structure / positive regulation of extracellular matrix organization / delta-catenin binding / B cell proliferation involved in immune response / Regulation of actin dynamics for phagocytic cup formation / neuroepithelial cell differentiation / microspike assembly / positive regulation of Wnt signaling pathway, planar cell polarity pathway / regulation of extracellular matrix organization / cerebellum morphogenesis / positive regulation of blood vessel branching / B-1 B cell homeostasis / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / Myogenesis / regulation of Cdc42 protein signal transduction / activated T cell proliferation / regulation of axon extension / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / alpha-beta T cell differentiation / syntaxin binding / cardiac muscle cell proliferation / regulation of T cell differentiation / negative regulation of double-strand break repair via homologous recombination / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cell-cell adhesion / regulation of microtubule polymerization / B cell proliferation / positive regulation of osteoblast proliferation / cell leading edge / negative regulation of cellular senescence / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of focal adhesion assembly / negative regulation of long-term synaptic potentiation / Bergmann glial cell differentiation / associative learning / neuromuscular process controlling balance / platelet-derived growth factor receptor signaling pathway / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / endothelial cell migration / positive regulation of T cell migration / BMP signaling pathway / canonical NF-kappaB signal transduction / phagocytosis / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / negative regulation of canonical NF-kappaB signal transduction / four-way junction DNA binding / signal transduction in response to DNA damage / positive regulation of vasoconstriction / spleen development / positive regulation of stress fiber assembly / ruffle / ERK1 and ERK2 cascade / cellular response to transforming growth factor beta stimulus / positive regulation of establishment of T cell polarity / positive regulation of interleukin-2 production / actin filament polymerization / SH2 domain binding / response to endoplasmic reticulum stress / phosphotyrosine residue binding / ephrin receptor binding / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / post-embryonic development / protein kinase C binding / positive regulation of release of sequestered calcium ion into cytosol / positive regulation of endothelial cell migration / thymus development / neural tube closure / integrin-mediated signaling pathway / establishment of localization in cell / regulation of actin cytoskeleton organization / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / epidermal growth factor receptor signaling pathway / negative regulation of ERK1 and ERK2 cascade / cell-cell adhesion / neuron differentiation / cellular response to hydrogen peroxide
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 / Src homology 3 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 / Src homology 3 domains / SH2 domain / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-FYH / Chem-STI / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 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 1.0Sep 12, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 10, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name

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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)68,8906
Polymers67,4872
Non-polymers1,4034
Water6,936385
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6534
Polymers33,7441
Non-polymers9093
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2372
Polymers33,7441
Non-polymers4941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.080, 65.201, 66.347
Angle α, β, γ (deg.)73.30, 79.82, 84.54
Int Tables number1
Space group name H-MP1

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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: 33743.523 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abl1, Abl / Production host: Spodoptera frugiperda (fall armyworm) / Variant (production host): SF9
References: UniProt: P00520, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-FYH / 3-(morpholin-4-ylmethyl)-~{N}-[4-(trifluoromethyloxy)phenyl]benzamide


Mass: 380.361 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19F3N2O3
#4: 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 / Imatinib


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


Mass: 18.015 Da / Num. of mol.: 385 / 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: 2.54 Å3/Da / Density % sol: 51.58 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 21.4 % 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: 0.9781 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Feb 22, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9781 Å / Relative weight: 1
ReflectionResolution: 2.3→37.34 Å / Num. obs: 27927 / % possible obs: 94.4 % / Redundancy: 1.99 % / Rmerge(I) obs: 0.048 / Net I/σ(I): 14.29
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 1.99 % / Rmerge(I) obs: 0.244 / Mean I/σ(I) obs: 3.16 / % possible all: 95.2

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Processing

Software
NameVersionClassification
REFMAC5.3.0040refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.3→35.25 Å / SU ML: 0.171 / Cross valid method: FREE R-VALUE / ESU R: 0.386 / ESU R Free: 0.25
RfactorNum. reflection% reflectionSelection details
Rfree0.23801 1397 5 %RANDOM
Rwork0.17471 ---
obs0.17795 26528 94.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 35.395 Å2
Baniso -1Baniso -2Baniso -3
1--0.78 Å2-0.01 Å20.21 Å2
2--0.48 Å2-0.69 Å2
3---0.63 Å2
Refinement stepCycle: LAST / Resolution: 2.3→35.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4612 0 102 385 5099
LS refinement shellResolution: 2.3→2.36 Å
RfactorNum. reflection% reflection
Rfree0.334 --
Rwork0.205 1990 -
obs--95.66 %

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