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- PDB-4zog: VX-680/MK-0457 binds to human ABL1 also in inactive DFG conformations. -

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Basic information

Entry
Database: PDB / ID: 4zog
TitleVX-680/MK-0457 binds to human ABL1 also in inactive DFG conformations.
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Kinase / ABL1 / DFG conformations
Function / homology
Function and homology information


positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DN4 thymocyte differentiation / DNA conformation change / 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 / protein localization to cytoplasmic microtubule plus-end / DN4 thymocyte differentiation / DNA conformation change / 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 / cerebellum morphogenesis / neuroepithelial cell differentiation / B cell proliferation involved in immune response / : / 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 / mitochondrial depolarization / bubble DNA binding / regulation of cell motility / positive regulation of establishment of T cell polarity / activated T cell proliferation / cellular response to dopamine / myoblast proliferation / positive regulation of blood vessel branching / proline-rich region binding / syntaxin binding / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / regulation of hematopoietic stem cell differentiation / 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 / cardiac muscle cell proliferation / negative regulation of cell-cell adhesion / HDR through Single Strand Annealing (SSA) / positive regulation of osteoblast proliferation / Myogenesis / platelet-derived growth factor receptor-beta signaling pathway / RUNX2 regulates osteoblast differentiation / regulation of microtubule polymerization / Fc-gamma receptor signaling pathway involved in phagocytosis / Bergmann glial cell differentiation / vascular endothelial cell response to oscillatory fluid shear stress / regulation of endocytosis / associative learning / negative regulation of cellular senescence / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / negative regulation of mitotic cell cycle / actin monomer binding / signal transduction in response to DNA damage / negative regulation of BMP signaling pathway / positive regulation of focal adhesion assembly / peptidyl-tyrosine autophosphorylation / RHO GTPases Activate WASPs and WAVEs / canonical NF-kappaB signal transduction / BMP signaling pathway / 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 / mismatch repair / regulation of cell adhesion / 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 endothelial cell migration / positive regulation of interleukin-2 production / substrate adhesion-dependent cell spreading / positive regulation of mitotic cell cycle / SH2 domain binding / protein kinase C binding / response to endoplasmic reticulum stress / positive regulation of release of sequestered calcium ion into cytosol / thymus development / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / integrin-mediated signaling pathway / post-embryonic development / B cell receptor signaling pathway
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
2-METHOXYETHANOL / Chem-VX6 / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsKyomuhendo, P. / Narayanan, D. / Engh, R.A.
Funding support Norway, 1items
OrganizationGrant numberCountry
Tromso Research Foundation Norway
CitationJournal: To Be Published
Title: VX-680/MK-0457 binds also to human ABL1 with inactive DFG conformations.
Authors: Kyomuhendo, P. / Narayanan, D. / Engh, R.A.
History
DepositionMay 6, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 14, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _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)66,8888
Polymers65,5352
Non-polymers1,3536
Water2,252125
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4605
Polymers32,7671
Non-polymers6934
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4273
Polymers32,7671
Non-polymers6602
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)105.937, 132.425, 56.551
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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: 32767.408 Da / Num. of mol.: 2 / Fragment: UNP residues 229-511
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Plasmid: pET28a-TEV / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-VX6 / CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE


Mass: 464.586 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H28N8OS / Comment: inhibitor*YM
#3: Chemical ChemComp-MXE / 2-METHOXYETHANOL


Mass: 76.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O2
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.18 Å3/Da / Density % sol: 61.37 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.6
Details: PEG MME2000 (31% w/v), MES (100 mM, pH 6.5) and sodium acetate (260mM).

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91705 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 8, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91705 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 36095 / % possible obs: 99.8 % / Redundancy: 4.09 % / Rmerge(I) obs: 0.1003 / Rsym value: 0.1 / Net I/σ(I): 12
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.784 / Mean I/σ(I) obs: 1.9 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
PHASER1.9_1692phasing
Aimless0.1.28data scaling
XDSJuly 4, 2012data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2G2H

2g2h


Resolution: 2.3→43.002 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.99 / Phase error: 23.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2332 1802 5 %Random selection
Rwork0.1842 ---
obs0.1867 36049 99.59 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→43.002 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4261 0 93 125 4479
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084464
X-RAY DIFFRACTIONf_angle_d1.16044
X-RAY DIFFRACTIONf_dihedral_angle_d17.2711629
X-RAY DIFFRACTIONf_chiral_restr0.041645
X-RAY DIFFRACTIONf_plane_restr0.005760
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2995-2.36160.30461380.2482623X-RAY DIFFRACTION100
2.3616-2.43110.30841350.24082559X-RAY DIFFRACTION100
2.4311-2.50960.31561370.23172608X-RAY DIFFRACTION100
2.5096-2.59930.29211380.21522619X-RAY DIFFRACTION100
2.5993-2.70330.22951360.20512598X-RAY DIFFRACTION100
2.7033-2.82630.23161390.20082630X-RAY DIFFRACTION100
2.8263-2.97530.26191380.19642615X-RAY DIFFRACTION100
2.9753-3.16170.27881380.21032622X-RAY DIFFRACTION100
3.1617-3.40570.25391370.19992613X-RAY DIFFRACTION100
3.4057-3.74820.21311400.16892662X-RAY DIFFRACTION100
3.7482-4.29020.22761400.15362653X-RAY DIFFRACTION100
4.2902-5.40350.17781410.14612691X-RAY DIFFRACTION100
5.4035-43.00920.19411450.17322754X-RAY DIFFRACTION97
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)
10.14180.22750.06780.35130.1760.1775-0.1852-0.20270.10680.0380.06940.0091-0.3047-0.11920.00010.4130.09250.02310.3613-0.02050.2181-18.768118.8475.525
20.4991-0.1379-0.06770.0404-0.04770.2197-0.2413-0.02360.04740.2910.12330.05110.059-0.2531-0.01130.24330.0806-0.01350.23970.00010.1793-24.990520.9767-2.4072
30.5742-0.43050.07770.27690.10830.8812-0.03580.0771-0.01350.06560.0462-0.0003-0.0766-0.0902-0.00060.16010.05160.0060.14810.01250.1687-17.905411.3138-16.5217
40.6896-0.3418-0.21860.47350.36310.5676-0.02070.3085-0.1069-0.1087-0.0239-0.02370.1627-0.21590.00010.15220.0104-0.00390.2204-0.03710.1446-17.35824.6298-28.7318
50.23440.20520.19940.26210.09980.11310.1081-0.08690.5197-0.0522-0.2559-0.2881-0.39910.1229-0.00150.2843-0.06170.05820.45470.05680.6562-17.741357.9293-11.6906
60.6032-0.3611-0.18030.31820.0780.20210.04980.16540.13140.0456-0.0371-0.2988-0.00050.1569-00.17990.0176-0.0130.24670.06580.2987-28.264744.6654-12.7552
70.0470.0180.06380.01030.04570.069-0.1286-0.10650.23790.14340.00370.0366-0.26760.09210.00010.64360.0343-0.06780.2752-0.08040.4321-36.591458.0655-3.1099
80.6261-0.11990.27970.5108-0.48330.462-0.01280.04620.02660.0269-0.068-0.01580.0081-0.0128-00.20160.0318-0.01340.14230.01110.1846-46.316244.8399-12.9513
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 233 through 264 )A233 - 264
2X-RAY DIFFRACTION2chain 'A' and (resid 265 through 310 )A265 - 310
3X-RAY DIFFRACTION3chain 'A' and (resid 311 through 444 )A311 - 444
4X-RAY DIFFRACTION4chain 'A' and (resid 445 through 501 )A445 - 501
5X-RAY DIFFRACTION5chain 'B' and (resid 234 through 292 )B234 - 292
6X-RAY DIFFRACTION6chain 'B' and (resid 293 through 379 )B293 - 379
7X-RAY DIFFRACTION7chain 'B' and (resid 380 through 401 )B380 - 401
8X-RAY DIFFRACTION8chain 'B' and (resid 402 through 503 )B402 - 503

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