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- PDB-8i7z: The crystal structure of human abl1 kinase domain in complex with... -

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Basic information

Entry
Database: PDB / ID: 8i7z
TitleThe crystal structure of human abl1 kinase domain in complex with ABL1-B5
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Covalent Kinase BCR-ABL
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 / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process ...: / positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / 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 / cerebellum morphogenesis / neuroepithelial cell differentiation / B cell proliferation involved in immune response / positive regulation of extracellular matrix organization / positive regulation of Wnt signaling pathway, planar cell polarity pathway / microspike assembly / B-1 B cell homeostasis / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / regulation of cell motility / mitochondrial depolarization / positive regulation of establishment of T cell polarity / activated T cell proliferation / cellular response to dopamine / positive regulation of blood vessel branching / proline-rich region binding / negative regulation of mitotic cell cycle / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / regulation of hematopoietic stem cell differentiation / syntaxin binding / alpha-beta T cell differentiation / positive regulation of dendrite development / positive regulation of cell migration involved in sprouting angiogenesis / peptidyl-tyrosine autophosphorylation / regulation of axon extension / positive regulation of peptidyl-tyrosine phosphorylation / regulation of T cell differentiation / negative regulation of cell-cell adhesion / HDR through Single Strand Annealing (SSA) / neuromuscular process controlling balance / Myogenesis / positive regulation of osteoblast proliferation / positive regulation of vasoconstriction / platelet-derived growth factor receptor-beta signaling pathway / RUNX2 regulates osteoblast differentiation / Fc-gamma receptor signaling pathway involved in phagocytosis / vascular endothelial cell response to oscillatory fluid shear stress / regulation of endocytosis / Bergmann glial cell differentiation / regulation of microtubule polymerization / myoblast proliferation / associative learning / negative regulation of long-term synaptic potentiation / negative regulation of cellular senescence / actin monomer binding / signal transduction in response to DNA damage / positive regulation of focal adhesion assembly / canonical NF-kappaB signal transduction / negative regulation of BMP signaling pathway / RHO GTPases Activate WASPs and WAVEs / cardiac muscle cell proliferation / ephrin receptor signaling pathway / positive regulation of T cell migration / endothelial cell migration / BMP signaling pathway / 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 / four-way junction DNA binding / ephrin receptor binding / spleen development / positive regulation of stress fiber assembly / ruffle / ERK1 and ERK2 cascade / actin filament polymerization / phosphotyrosine residue binding / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of interleukin-2 production / positive regulation of endothelial cell migration / SH2 domain binding / substrate adhesion-dependent cell spreading / positive regulation of mitotic cell cycle / protein kinase C binding / response to endoplasmic reticulum stress / peptidyl-tyrosine phosphorylation / 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
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
: / BETA-ALANINE / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25495806781 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 23, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)64,1845
Polymers63,3182
Non-polymers8663
Water4,918273
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1373
Polymers31,6591
Non-polymers4782
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)104.603, 133.37, 56.554
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

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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: Chemical ChemComp-BAL / BETA-ALANINE


Type: peptide-like / Mass: 89.093 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H7NO2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 273 / 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: 3.12 Å3/Da / Density % sol: 60.57 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.5M (NH4)2 SO4, 0.1M 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: 2.25→66.69 Å / Num. obs: 60553 / % possible obs: 99.1 % / Redundancy: 7.4 % / Biso Wilson estimate: 29.7515645732 Å2 / CC1/2: 0.992 / Net I/σ(I): 1.31
Reflection shellResolution: 2.25→2.3 Å / Num. unique obs: 60553 / CC1/2: 0.992

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
HKL-3000data reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25495806781→66.685 Å / SU ML: 0.170539767783 / Cross valid method: FREE R-VALUE / σ(F): 1.35017444663 / Phase error: 20.5083808977
RfactorNum. reflection% reflection
Rfree0.213408196047 1252 3.28919714166 %
Rwork0.175473497035 36812 -
obs0.176724497406 38064 99.8557149978 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 41.9352380218 Å2
Refinement stepCycle: LAST / Resolution: 2.25495806781→66.685 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4176 0 64 273 4513
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002200984741184352
X-RAY DIFFRACTIONf_angle_d0.6737048242715918
X-RAY DIFFRACTIONf_chiral_restr0.0260174080965635
X-RAY DIFFRACTIONf_plane_restr0.00238472280976741
X-RAY DIFFRACTIONf_dihedral_angle_d15.38154163361561
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.255-2.34520.2599534755691360.2121314104894010X-RAY DIFFRACTION99.8795470971
2.3452-2.4520.2681067842531380.2081529351344042X-RAY DIFFRACTION99.976082277
2.452-2.58130.2530565637621370.2039599489264039X-RAY DIFFRACTION99.9760593728
2.5813-2.7430.2208199621841370.202574600894043X-RAY DIFFRACTION99.976082277
2.743-2.95480.2532112434221380.2015804769864062X-RAY DIFFRACTION99.9761961438
2.9548-3.25210.2423242794751390.1872934364994067X-RAY DIFFRACTION99.9762300927
3.2521-3.72270.1736880484491390.1628522492384116X-RAY DIFFRACTION99.929544387
3.7227-4.690.1929194769581420.1429208023344138X-RAY DIFFRACTION99.9532928538
4.69-66.60.1918571035881460.1651026832934295X-RAY DIFFRACTION99.1294642857
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)
14.67619422869-1.848638522162.699140118593.042927788550.09974199799984.74847388165-0.134732195892-0.3848362655140.4029304418290.3091842580940.02790267432250.159745329238-0.412411611755-0.272918552850.05477808478090.2490350274810.06313824923610.05616297148780.25195383501-0.03098926610940.18745748963-22.720966727320.14217851232.7501405413
22.90371587759-0.760634470509-0.490596671831.970843443330.8836281150332.44589617422-0.0665769982507-0.0942440334418-0.02942317382630.1204490940270.003077524440640.158069287798-0.109312851823-0.1642357149870.04394190147980.1446416584790.04640827435550.01646598969640.1539951182750.03230587479220.114677587256-18.84523434238.46709360878-9.06309256476
35.75757402117-0.878289170972-2.813422995421.8318546919-0.1709981739624.88536367892-0.001067551133160.0589743613790.4765995328870.1389122814190.03111404743770.146644195331-0.193270163652-0.376953226889-0.002196637240780.2625665565470.109917969039-0.003229409147070.228308574434-0.025978589330.233436106307-23.596006831520.9762967648-23.2863206916
43.764512891430.466557005344-0.827057803132.70510570833-0.7603795334154.358688992620.01594456402160.218017874665-0.256421721278-0.246591702752-0.105818581692-0.0675692532770.220878578075-0.09837557051940.07719263463140.159510230760.05951403940950.008720284031080.170642175308-0.03661815775750.111614120563-15.9291818266.36078360192-27.8486924851
51.463553315440.984774989729-1.111065343121.783620418950.6459445032133.3332633520.1163050530320.2431654890790.0721986891796-0.2977326891080.239420719627-0.925888458282-0.7875017477611.1672119168-0.225457235180.45946357223-0.1466463228680.02797300300340.708609089904-0.05811961143940.835723371308-16.283271402456.8867513459-11.2381891141
63.037205589620.8883377273480.4473381698783.194679663750.8860075943493.939242502490.01950465720190.04393221024140.295707955176-0.02771025258010.00646360230206-0.599968600076-0.2874610530610.474601121184-0.04773444743640.2139188582090.063781783117-0.05487290726860.2554324495440.01537907334920.397830933615-27.24496660744.9627007557-12.3700073482
78.94721131966-5.08057452843-2.164401216969.337097899843.313408506152.157304451960.4027417801860.05758614238390.780976607193-0.502314757519-0.27248435011-0.539961052125-0.7462542376640.504623783868-0.156120171660.467593343185-0.01460358893930.007951414900930.349005781377-0.1060521875380.435345094441-34.851011552758.5490019327-1.7501586367
84.10666180113-1.654299977030.1991658798673.08174729169-0.7272825388052.19267990442-0.104722832195-0.06724331882240.1379303222170.07470579698830.0275458201876-0.0586670646592-0.102891422687-0.08850888386850.05159247389740.2352238651050.0605776891614-0.07223668423750.18477624788-0.05132014242720.162215864081-45.956015382745.4436849736-12.3471844766
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 499 )
5X-RAY DIFFRACTION5chain 'B' and (resid 232 through 292 )
6X-RAY DIFFRACTION6chain 'B' and (resid 293 through 379 )
7X-RAY DIFFRACTION7chain 'B' and (resid 380 through 400 )
8X-RAY DIFFRACTION8chain 'B' and (resid 401 through 500 )

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