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- PDB-8h7h: The crystal structure of human abl1 kinase domain in complex with... -

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Basic information

Entry
Database: PDB / ID: 8h7h
TitleThe crystal structure of human abl1 kinase domain in complex with abl1-A-EBA
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Complex / inhibitor / lysine
Function / homology
Function and homology information


: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine / transitional one stage B cell differentiation ...: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine / transitional one stage B cell differentiation / activation of protein kinase C activity / nicotinate-nucleotide adenylyltransferase activity / regulation of modification of synaptic structure / positive regulation of microtubule binding / delta-catenin binding / B cell proliferation involved in immune response / positive regulation of extracellular matrix organization / neuroepithelial cell differentiation / microspike assembly / positive regulation of Wnt signaling pathway, planar cell polarity pathway / cerebellum morphogenesis / positive regulation of blood vessel branching / B-1 B cell homeostasis / mitochondrial depolarization / negative regulation of ubiquitin-protein transferase activity / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / negative regulation of protein serine/threonine kinase activity / activated T cell proliferation / cellular response to dopamine / regulation of cell motility / regulation of Cdc42 protein signal transduction / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / regulation of hematopoietic stem cell differentiation / alpha-beta T cell differentiation / syntaxin binding / cardiac muscle cell proliferation / regulation of axon extension / regulation of T cell differentiation / HDR through Single Strand Annealing (SSA) / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cell-cell adhesion / Fc-gamma receptor signaling pathway involved in phagocytosis / Myogenesis / regulation of microtubule polymerization / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / platelet-derived growth factor receptor-beta signaling pathway / negative regulation of cellular senescence / positive regulation of focal adhesion assembly / associative learning / Bergmann glial cell differentiation / neuromuscular process controlling balance / regulation of endocytosis / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / negative regulation of long-term synaptic potentiation / actin monomer binding / endothelial cell migration / RHO GTPases Activate WASPs and WAVEs / positive regulation of T cell migration / canonical NF-kappaB signal transduction / signal transduction in response to DNA damage / negative regulation of double-strand break repair via homologous recombination / regulation of cell adhesion / BMP signaling pathway / mismatch repair / negative regulation of endothelial cell apoptotic process / four-way junction DNA binding / peptidyl-tyrosine autophosphorylation / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of vasoconstriction / spleen development / positive regulation of stress fiber assembly / cellular response to transforming growth factor beta stimulus / ruffle / positive regulation of establishment of T cell polarity / positive regulation of interleukin-2 production / ERK1 and ERK2 cascade / ephrin receptor binding / actin filament polymerization / phosphotyrosine residue binding / response to endoplasmic reticulum stress / positive regulation of endothelial cell migration / SH2 domain binding / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / positive regulation of release of sequestered calcium ion into cytosol / post-embryonic development / thymus development / regulation of autophagy / neural tube closure / establishment of localization in cell / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / protein kinase C binding
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 / Src homology 3 domains ...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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-QH9 / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.27789711576 Å
AuthorsZhu, C.J. / Zhang, Z.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Am.Chem.Soc. / Year: 2023
Title: 2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases.
Authors: Chen, P. / Tang, G. / Zhu, C. / Sun, J. / Wang, X. / Xiang, M. / Huang, H. / Wang, W. / Li, L. / Zhang, Z.M. / Gao, L. / Yao, S.Q.
History
DepositionOct 20, 2022Deposition site: PDBJ / Processing site: PDBE
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.2Feb 7, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)65,0204
Polymers64,1252
Non-polymers8952
Water8,539474
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5102
Polymers32,0631
Non-polymers4471
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5102
Polymers32,0631
Non-polymers4471
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.766, 104.777, 133.014
Angle α, β, γ (deg.)90.0, 90.0, 90.0
Int Tables number18
Space group name H-MP22121
Space group name HallP22ab(z,x,y)
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y+1/2,-z+1/2
#4: -x,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-884-

HOH

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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: 32062.590 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 (E. coli)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-QH9 / 5-[3-(6-methoxyisoquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-methyl-N-prop-2-ynyl-pyridine-3-carboxamide


Mass: 447.488 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H21N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 474 / Source method: isolated from a natural source / Formula: H2O
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: 3.06 Å3/Da / Density % sol: 59.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.5 M (NH4)2SO4, 0.1 M HEPES (pH 7.0) and 4% v/v 1,3-propanediol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Sep 3, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 34902 / % possible obs: 99.9 % / Redundancy: 7.4 % / CC1/2: 0.992 / Net I/σ(I): 17
Reflection shellResolution: 2.2→2.28 Å / Num. unique obs: 34902 / CC1/2: 0.983

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
HKL-3000data reduction
XDSdata scaling
PHENIXphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7W7Y

7w7y


Resolution: 2.27789711576→26.19425 Å / SU ML: 0.22645577164 / Cross valid method: FREE R-VALUE / σ(F): 1.36209744713 / Phase error: 20.6252877236
RfactorNum. reflection% reflection
Rfree0.220547655789 1981 5.675892499 %
Rwork0.182442800513 32921 -
obs0.184642829412 34902 94.1795515259 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.6573189228 Å2
Refinement stepCycle: LAST / Resolution: 2.27789711576→26.19425 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4263 0 0 474 4737
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003012203617494377
X-RAY DIFFRACTIONf_angle_d0.7011032973325951
X-RAY DIFFRACTIONf_chiral_restr0.0276778235447632
X-RAY DIFFRACTIONf_plane_restr0.00253164278745746
X-RAY DIFFRACTIONf_dihedral_angle_d16.29382076011578
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2779-2.33480.245913230435550.199816862808917X-RAY DIFFRACTION37.5
2.3348-2.39790.2769357012761460.201081545912427X-RAY DIFFRACTION99.6514329977
2.3979-2.46840.2310834566891490.1923895950382486X-RAY DIFFRACTION99.8106060606
2.4684-2.5480.2643510095341480.1962395462252456X-RAY DIFFRACTION99.9616122841
2.548-2.6390.2626542830661460.1957611930412436X-RAY DIFFRACTION99.8839458414
2.639-2.74460.2489789905581480.196193623962475X-RAY DIFFRACTION99.847735059
2.7446-2.86930.2355723608831490.2034349595062477X-RAY DIFFRACTION99.9238964992
2.8693-3.02040.2417909052571490.1918803601952477X-RAY DIFFRACTION99.8858881704
3.0204-3.20930.2230155694891500.1882274061672489X-RAY DIFFRACTION99.9242711094
3.2093-3.45660.2043872197191470.1760424354792483X-RAY DIFFRACTION99.7345468335
3.4566-3.80350.1936870232531510.1626791357632512X-RAY DIFFRACTION99.6631736527
3.8035-4.35170.1768900479061520.1595399753432504X-RAY DIFFRACTION99.141470698
4.3517-5.47450.1866449559041510.1669828709512462X-RAY DIFFRACTION96.7777777778
5.4745-26.19410.2211743300211400.1817912635992320X-RAY DIFFRACTION86.5892291447
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)
11.26353669342-0.7323724461730.04466656354230.502642185909-0.1000416677440.8808452906410.08754671562850.1871879443750.0268097427391-0.162889960301-0.164048727439-0.266486228143-0.02530926978970.2491581636660.03198792815480.16191369636-0.031345102723-0.006508613831220.2518661237440.1134389221550.31937534961.0155214767922.7085032333-19.9183067206
20.1984813506760.0533799722883-0.07226157022030.63591114254-0.1873617827380.7484755368760.001038199344670.0704667504970.1438355043590.0788257988317-0.108663304958-0.147277026339-0.0950423574140.06918173509180.02183885716270.112161284485-0.0124331088992-0.05091117865310.08956350126160.0767714199550.105280395439-13.024757707819.1260780068-9.93251907861
30.9018586892220.008208956913190.2648116112761.26286414501-0.04379118048990.617346622189-0.00775723412448-0.1437052509360.1048402608530.2000741591850.04926985648810.206419624720.0248725751203-0.285394656282-0.003657309757180.06077140179-0.006432952697060.002917439631870.1082103863560.02118265107530.0773034883881-27.802554273616.1761697832-8.70786299172
40.22392783380.3423964194340.2339478756130.5248007194320.3595603883920.252815762470.02763564323580.211026391503-0.504401182146-0.151810819547-0.09991152648050.1786446078150.268375560425-0.01732314775420.03098644534350.7491661921130.00310311384665-0.02591765020120.525795453552-0.132859704910.674465607223-13.314031425214.9719618429-56.6217573938
51.148210929920.09653041558380.3313844173721.178941524831.300371111892.24200221929-0.07970763486310.329017446879-0.449674655222-0.290473168335-0.02572110900350.1079633978640.442734645203-0.1867950437480.09611874941970.581143319740.04969300780690.1128659922150.295041793786-0.08733616611680.398983331285-8.5411662414617.9524586947-53.9614616568
61.310432856780.0872092402823-0.4954609773850.6727753802-0.2909691533991.11043568774-0.05624795743530.170433264231-0.166418683825-0.2729847682850.0240448550355-0.01369081683020.28791942633-0.0670591601252-0.01709392451370.2035121261840.05780232799420.01758486789070.1834760967970.0714658632110.157317436164-13.96191590529.6571537581-42.5569651621
70.1934343253380.126075495392-0.1846822299920.284559319905-0.09560467662310.1944750323850.08096658299740.2998542000670.0508700856895-0.391567354392-0.0632923319076-0.151905062231-0.074191763728-0.04897781155570.01827062453920.2771908158520.1588315973530.1348677961810.3009723563070.241046557022-0.0309694713046-11.065473238742.579699629-53.6595004819
80.258563874633-0.3288551022620.3487167275820.709435154652-0.516260012510.6615342455810.06571031070680.03898298408730.114436457110.0684693514058-0.0311548549359-0.138095843019-0.0862257654823-0.0737341327638-0.001787855028280.1070979736890.1291316386710.01474385864640.153157619530.1692368935490.201512467772-10.527559286646.2329003292-38.9579591645
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 232 through 311 )
2X-RAY DIFFRACTION2chain 'A' and (resid 312 through 400 )
3X-RAY DIFFRACTION3chain 'A' and (resid 401 through 500 )
4X-RAY DIFFRACTION4chain 'B' and (resid 232 through 255 )
5X-RAY DIFFRACTION5chain 'B' and (resid 256 through 312 )
6X-RAY DIFFRACTION6chain 'B' and (resid 313 through 379 )
7X-RAY DIFFRACTION7chain 'B' and (resid 380 through 453 )
8X-RAY DIFFRACTION8chain 'B' and (resid 454 through 500 )

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