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- PDB-8i7s: The crystal structure of human abl1 kinase domain in complex with... -

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Basic information

Entry
Database: PDB / ID: 8i7s
TitleThe crystal structure of human abl1 kinase domain in complex with ABL1-B1
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Covalent Kinase BCR-ABL
Function / homology
Function and homology information


positive regulation of actin filament binding / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / activation of protein kinase C activity / DN4 thymocyte differentiation / response to epinephrine / podocyte apoptotic process / transitional one stage B cell differentiation / DNA conformation change ...positive regulation of actin filament binding / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / activation of protein kinase C activity / DN4 thymocyte differentiation / response to epinephrine / podocyte apoptotic process / transitional one stage B cell differentiation / DNA conformation change / Role of ABL in ROBO-SLIT signaling / nicotinate-nucleotide adenylyltransferase activity / regulation of modification of synaptic structure / positive regulation of microtubule binding / delta-catenin binding / positive regulation of extracellular matrix organization / B cell proliferation involved in immune response / 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 / negative regulation of ubiquitin-protein transferase activity / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / mitochondrial depolarization / negative regulation of protein serine/threonine kinase activity / activated T cell proliferation / cellular response to dopamine / regulation of hematopoietic stem cell differentiation / regulation of cell motility / proline-rich region binding / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / positive regulation of dendrite development / myoblast proliferation / syntaxin binding / alpha-beta T cell differentiation / cardiac muscle cell proliferation / regulation of T cell differentiation / regulation of axon extension / Fc-gamma receptor signaling pathway involved in phagocytosis / HDR through Single Strand Annealing (SSA) / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cell-cell adhesion / Myogenesis / positive regulation of osteoblast proliferation / regulation of microtubule polymerization / 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 / regulation of endocytosis / neuromuscular process controlling balance / negative regulation of mitotic cell cycle / negative regulation of long-term synaptic potentiation / actin monomer binding / negative regulation of BMP signaling pathway / negative regulation of double-strand break repair via homologous recombination / endothelial cell migration / signal transduction in response to DNA damage / positive regulation of T cell migration / RHO GTPases Activate WASPs and WAVEs / mismatch repair / regulation of cell adhesion / BMP signaling pathway / negative regulation of endothelial cell apoptotic process / canonical NF-kappaB signal transduction / peptidyl-tyrosine autophosphorylation / positive regulation of substrate adhesion-dependent cell spreading / four-way junction DNA binding / spleen development / positive regulation of vasoconstriction / cellular response to transforming growth factor beta stimulus / positive regulation of stress fiber assembly / ruffle / response to endoplasmic reticulum stress / positive regulation of establishment of T cell polarity / phosphotyrosine residue binding / ephrin receptor binding / positive regulation of interleukin-2 production / ERK1 and ERK2 cascade / actin filament polymerization / SH2 domain binding / positive regulation of endothelial cell migration / post-embryonic development / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / thymus development / positive regulation of release of sequestered calcium ion into cytosol / integrin-mediated signaling pathway / regulation of autophagy / establishment of localization in cell / neural tube closure / regulation of actin cytoskeleton organization / non-specific protein-tyrosine kinase
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 / 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
: / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94635467805 Å
AuthorsZhu, C. / Zhang, Z.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Adv Res / Year: 2024
Title: Rationally designed BCR-ABL kinase inhibitors for improved leukemia treatment via covalent and pro-/dual-drug targeting strategies.
Authors: Sun, J. / Lou, L. / Zhu, C. / Chen, P. / Tang, G. / Gu, M. / Xia, S. / Dong, X. / Zhang, Z.M. / Gao, L. / Yao, S.Q. / Xiao, Q.
History
DepositionFeb 2, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release

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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)64,0954
Polymers63,3182
Non-polymers7772
Water8,575476
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0482
Polymers31,6591
Non-polymers3881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0482
Polymers31,6591
Non-polymers3881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.461, 132.635, 56.1974
Angle α, β, γ (deg.)90.0, 90.0, 90.0
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z
Components on special symmetry positions
IDModelComponents
11A-892-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11TYRTYRLEULEUchain 'A'AA232 - 2484 - 20
12GLYGLYLEULEUchain 'A'AA254 - 27326 - 45
13VALVALTHRTHRchain 'A'AA280 - 39252 - 164
14THRTHRSERSERchain 'A'AA394 - 500166 - 272
25TYRTYRLEULEUchain 'B'BB232 - 2484 - 20
26GLYGLYLEULEUchain 'B'BB254 - 27326 - 45
27VALVALTHRTHRchain 'B'BB280 - 39252 - 164
28THRTHRSERSERchain 'B'BB394 - 500166 - 272

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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: 31659.131 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 (bacteria)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-6CI / 5-[3-(2-methoxy-5-oxidanyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-pyridine-3-carboxamide


Mass: 388.419 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H20N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 476 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.07 Å3/Da / Density % sol: 59.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.5M (NH4)2SO4, 0.1M HEPES (PH 7.0), 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 5, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.94→40.72 Å / Num. obs: 57806 / % possible obs: 99.54 % / Redundancy: 4.6 % / CC1/2: 0.996 / Net I/σ(I): 7.25
Reflection shellResolution: 1.95→2.02 Å / Num. unique obs: 57806 / CC1/2: 0.745

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
PHENIX1.9_1692+SVNrefinement
HKL-3000data reduction
XDSdata scaling
PHENIXphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.94635467805→40.7151710362 Å / SU ML: 0.185315864213 / Cross valid method: FREE R-VALUE / σ(F): 1.3430750431 / Phase error: 21.2403006463
RfactorNum. reflection% reflection
Rfree0.21563453186 2881 4.99220239127 %
Rwork0.184633302135 54829 -
obs0.186216017816 57710 99.390327914 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 35.9672045812 Å2
Refinement stepCycle: LAST / Resolution: 1.94635467805→40.7151710362 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4228 0 58 476 4762
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007387002398944398
X-RAY DIFFRACTIONf_angle_d1.089555529625968
X-RAY DIFFRACTIONf_chiral_restr0.0463503263998634
X-RAY DIFFRACTIONf_plane_restr0.00515795732854747
X-RAY DIFFRACTIONf_dihedral_angle_d15.77495448231598
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9464-1.97830.2587316305741200.2506328789492328X-RAY DIFFRACTION89.9338721528
1.9783-2.01240.303128945961440.2389714666832579X-RAY DIFFRACTION99.6341017197
2.0124-2.0490.26572272521340.2231100986372555X-RAY DIFFRACTION99.335057259
2.049-2.08840.2555335691721450.2218060933382590X-RAY DIFFRACTION99.7811017877
2.0884-2.1310.2136450407551280.1995018413492576X-RAY DIFFRACTION99.778597786
2.131-2.17730.2056390720051350.1941664980452602X-RAY DIFFRACTION99.8176513494
2.1773-2.2280.2348987069151520.1974032743112582X-RAY DIFFRACTION99.9269005848
2.228-2.28370.2093151593551430.2116333072262601X-RAY DIFFRACTION99.7455470738
2.2837-2.34540.2366107894841350.1892664810172583X-RAY DIFFRACTION99.9632217727
2.3454-2.41440.2095427878761170.1844313596452618X-RAY DIFFRACTION99.8175182482
2.4144-2.49240.2342619488261440.1835627576982578X-RAY DIFFRACTION99.9632757988
2.4924-2.58140.2069660432051320.1820492589382645X-RAY DIFFRACTION99.9280316661
2.5814-2.68480.2082641286041310.1874649457982610X-RAY DIFFRACTION99.9270871309
2.6848-2.80690.2192662869031320.1852224739482624X-RAY DIFFRACTION99.9274836838
2.8069-2.95490.2389808508971220.1892192641362646X-RAY DIFFRACTION99.9638858794
2.9549-3.13990.203517254531450.1830768683332617X-RAY DIFFRACTION100
3.1399-3.38230.2036267930861290.1680473044792649X-RAY DIFFRACTION100
3.3823-3.72240.1969771427571440.15573051212656X-RAY DIFFRACTION100
3.7224-4.26060.1726109272821480.152309397522668X-RAY DIFFRACTION100
4.2606-5.36590.1803641512411380.1648795030662701X-RAY DIFFRACTION99.9647887324
5.3659-40.70.2476752517731630.2048471772722821X-RAY DIFFRACTION99.6992983628
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)
14.29298217738-2.441826256553.5646072843.02969854666-0.4268130675264.53933538816-0.108385082198-0.230588393590.3881774637730.200877290144-0.05360345894970.0395693344844-0.250455891757-0.2080997835280.116295174230.2100559214530.05208949780820.03335898477930.227136245995-0.01512831883350.156895143107-22.391019143320.25539800982.43930754276
22.09063423255-0.80660307302-0.4388876009231.634383073130.5261776169841.75389611735-0.0873316163674-0.105369775359-0.01306423180810.1016784392960.07024891422980.108930641519-0.0766916887181-0.1146980416350.007108294660510.1216852457710.0452095600535-0.001048620301040.1457209082810.02446512311880.0953432375718-18.93250465728.64609610553-8.86271342731
33.67349647502-0.699402544937-1.725952655951.5773809047-0.2528498486753.11846040832-0.08884981006950.06865094159360.2509376131590.1046926957680.02865449188050.188453933146-0.104027333204-0.28908508201-0.05273830653780.2631610143730.1166469171710.01654694741180.194654087267-0.00990259167980.202365473113-23.263805975421.0605910038-23.0459682525
42.701275163220.279670638238-0.1764442221871.92534397856-0.3456661815223.377577582660.02741603107240.178246480245-0.241529989904-0.221480769483-0.0434621915465-0.08076825955510.210085078512-0.07506384109580.01432962450540.1397457405770.06475434434170.009627166028370.144001787266-0.02002438970870.100401391487-15.79963173256.20716996259-27.5491304181
52.438352579510.6482312930090.4286831238742.916126203711.280784303013.564627182380.01026628918480.07112860088140.339581406836-0.1612252549160.160412206579-0.708847280609-0.5706205755850.64201799835-0.1130614147920.316612215987-0.000277239572811-0.03638083862980.286673820728-0.01882299508030.456504727813-22.977848785349.2078006594-11.8726183586
62.45096973058-0.2198228300820.3205923082550.840126892038-0.1583344757541.72803833523-0.133698031755-0.1373925531970.302696180680.04187717465750.0133502358805-0.0810128246082-0.140260297826-0.02961412119480.09327352702080.2807554535590.106923142814-0.08271326169030.196076423304-0.05841643366840.197545293768-44.12693805747.348236943-10.6252460671
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 232 through 292 )
2X-RAY DIFFRACTION2chain 'A' and (resid 293 through 379 )
3X-RAY DIFFRACTION3chain 'A' and (resid 380 through 417 )
4X-RAY DIFFRACTION4chain 'A' and (resid 418 through 500 )
5X-RAY DIFFRACTION5chain 'B' and (resid 232 through 379 )
6X-RAY DIFFRACTION6chain 'B' and (resid 380 through 500 )

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