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- PDB-6npv: C-abl Kinase domain with the activator(cmpd51), N-(1-(3,4-dichlor... -

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Basic information

Entry
Database: PDB / ID: 6npv
TitleC-abl Kinase domain with the activator(cmpd51), N-(1-(3,4-dichlorophenyl)-4-(2-hydroxyethyl)-4,5-dihydro-1H-pyrazol-3-yl)isonicotinamide
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / activator / kinase / allosteric / SIGNALING PROTEIN
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 / : / 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 / SH2 domain superfamily / Src homology 3 domains / 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-KWP / Chem-STI / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
Authorscampobasso, N.
Citation
Journal: J. Med. Chem. / Year: 2019
Title: Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies.
Authors: Simpson, G.L. / Bertrand, S.M. / Borthwick, J.A. / Campobasso, N. / Chabanet, J. / Chen, S. / Coggins, J. / Cottom, J. / Christensen, S.B. / Dawson, H.C. / Evans, H.L. / Hobbs, A.N. / Hong, ...Authors: Simpson, G.L. / Bertrand, S.M. / Borthwick, J.A. / Campobasso, N. / Chabanet, J. / Chen, S. / Coggins, J. / Cottom, J. / Christensen, S.B. / Dawson, H.C. / Evans, H.L. / Hobbs, A.N. / Hong, X. / Mangatt, B. / Munoz-Muriedas, J. / Oliff, A. / Qin, D. / Scott-Stevens, P. / Ward, P. / Washio, Y. / Yang, J. / Young, R.J.
#1: Journal: Chem. Biol. / Year: 2011
Title: Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.
Authors: Yang, J. / Campobasso, N. / Biju, M.P. / Fisher, K. / Pan, X.Q. / Cottom, J. / Galbraith, S. / Ho, T. / Zhang, H. / Hong, X. / Ward, P. / Hofmann, G. / Siegfried, B. / Zappacosta, F. / ...Authors: Yang, J. / Campobasso, N. / Biju, M.P. / Fisher, K. / Pan, X.Q. / Cottom, J. / Galbraith, S. / Ho, T. / Zhang, H. / Hong, X. / Ward, P. / Hofmann, G. / Siegfried, B. / Zappacosta, F. / Washio, Y. / Cao, P. / Qu, J. / Bertrand, S. / Wang, D.Y. / Head, M.S. / Li, H. / Moores, S. / Lai, Z. / Johanson, K. / Burton, G. / Erickson-Miller, C. / Simpson, G. / Tummino, P. / Copeland, R.A. / Oliff, A.
History
DepositionJan 18, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
Item: _chem_comp.pdbx_synonyms / _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
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,05012
Polymers69,4172
Non-polymers2,63310
Water4,702261
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6774
Polymers34,7091
Non-polymers9693
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3728
Polymers34,7091
Non-polymers1,6647
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.973, 95.287, 115.361
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 34708.566 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: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: P00519, non-specific protein-tyrosine kinase

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Non-polymers , 6 types, 271 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: 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
#4: Chemical ChemComp-KWP / ~{N}-[(4~{S})-2-(3,4-dichlorophenyl)-4-(2-hydroxyethyl)-3,4-dihydropyrazol-5-yl]pyridine-4-carboxamide


Mass: 379.241 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H16Cl2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-2PE / NONAETHYLENE GLYCOL


Mass: 414.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H38O10 / Comment: precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / 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: 2.97 Å3/Da / Density % sol: 58.56 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 1 - 3 % PEG 400 0.1 HEPES pH 7.5 2M AmSO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 8, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.86→74.97 Å / Num. obs: 70192 / % possible obs: 99.9 % / Redundancy: 6.2 % / Biso Wilson estimate: 23.01 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.099 / Rpim(I) all: 0.043 / Rrim(I) all: 0.108 / Net I/σ(I): 12.3 / Num. measured all: 433918
Reflection shellResolution: 1.86→1.96 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.774 / Num. measured all: 63149 / Num. unique obs: 10130 / CC1/2: 0.848 / Rpim(I) all: 0.328 / Rrim(I) all: 0.842 / Net I/σ(I) obs: 2.6 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIXrefinement
Aimless0.5.32data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.86→45.716 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 19.33 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2066 3496 4.99 %
Rwork0.1817 66606 -
obs0.1829 70102 99.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 79.11 Å2 / Biso mean: 27.6141 Å2 / Biso min: 11.14 Å2
Refinement stepCycle: final / Resolution: 1.86→45.716 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4226 0 179 261 4666
Biso mean--31.05 29.77 -
Num. residues----521
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074530
X-RAY DIFFRACTIONf_angle_d0.936120
X-RAY DIFFRACTIONf_chiral_restr0.054629
X-RAY DIFFRACTIONf_plane_restr0.005773
X-RAY DIFFRACTIONf_dihedral_angle_d10.33171
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 25

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.86-1.88370.31031390.259726162755100
1.8837-1.91060.28361250.238226602785100
1.9106-1.93910.24531400.227926222762100
1.9391-1.96940.24621410.210526592800100
1.9694-2.00170.21591340.206526062740100
2.0017-2.03620.24511470.188526462793100
2.0362-2.07320.21091300.187626432773100
2.0732-2.11310.17841570.177526222779100
2.1131-2.15620.19781430.179526522795100
2.1562-2.20310.18451290.177826762805100
2.2031-2.25440.18981390.178826242763100
2.2544-2.31070.20681460.177226332779100
2.3107-2.37320.18891270.180126772804100
2.3732-2.4430.2021420.182426322774100
2.443-2.52190.20211270.189126752802100
2.5219-2.6120.22851430.184426482791100
2.612-2.71660.24021470.186226442791100
2.7166-2.84020.18431290.185326712800100
2.8402-2.98990.25531480.18926772825100
2.9899-3.17720.19761490.18126602809100
3.1772-3.42240.18951430.18412680282399
3.4224-3.76670.19931150.168727032818100
3.7667-4.31140.19221560.158226942850100
4.3114-5.43050.1831420.16352742288499
5.4305-45.73010.20941580.18872844300299

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