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- PDB-7ote: Src Kinase Domain in complex with ponatinib -

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Basic information

Entry
Database: PDB / ID: 7ote
TitleSrc Kinase Domain in complex with ponatinib
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsONCOPROTEIN / ATP Inhibitor / Kinase / ligand binding / Cell signalling
Function / homology
Function and homology information


positive regulation of non-membrane spanning protein tyrosine kinase activity / primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / regulation of toll-like receptor 3 signaling pathway / positive regulation of ovarian follicle development / positive regulation of platelet-derived growth factor receptor-beta signaling pathway / cellular response to prolactin / positive regulation of male germ cell proliferation / dendritic filopodium / regulation of cell projection assembly ...positive regulation of non-membrane spanning protein tyrosine kinase activity / primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / regulation of toll-like receptor 3 signaling pathway / positive regulation of ovarian follicle development / positive regulation of platelet-derived growth factor receptor-beta signaling pathway / cellular response to prolactin / positive regulation of male germ cell proliferation / dendritic filopodium / regulation of cell projection assembly / response to mineralocorticoid / positive regulation of dephosphorylation / ERBB2 signaling pathway / Regulation of commissural axon pathfinding by SLIT and ROBO / regulation of epithelial cell migration / positive regulation of protein transport / Regulation of gap junction activity / BMP receptor binding / positive regulation of lamellipodium morphogenesis / cellular response to progesterone stimulus / regulation of vascular permeability / positive regulation of protein processing / positive regulation of integrin activation / Activated NTRK2 signals through FYN / negative regulation of focal adhesion assembly / skeletal muscle cell proliferation / : / Netrin mediated repulsion signals / regulation of intracellular estrogen receptor signaling pathway / intestinal epithelial cell development / CD28 co-stimulation / positive regulation of glucose metabolic process / transcytosis / osteoclast development / Activated NTRK3 signals through PI3K / connexin binding / cellular response to fluid shear stress / response to acidic pH / focal adhesion assembly / signal complex assembly / positive regulation of small GTPase mediated signal transduction / positive regulation of Ras protein signal transduction / odontogenesis / positive regulation of podosome assembly / regulation of bone resorption / Regulation of RUNX1 Expression and Activity / branching involved in mammary gland duct morphogenesis / adherens junction organization / DCC mediated attractive signaling / EPH-Ephrin signaling / myoblast proliferation / Ephrin signaling / cellular response to peptide hormone stimulus / negative regulation of mitochondrial depolarization / podosome / Signal regulatory protein family interactions / cellular response to fatty acid / MET activates PTK2 signaling / Fc-gamma receptor signaling pathway involved in phagocytosis / regulation of early endosome to late endosome transport / Regulation of KIT signaling / postsynaptic specialization, intracellular component / Signaling by ALK / leukocyte migration / GP1b-IX-V activation signalling / CTLA4 inhibitory signaling / oogenesis / phospholipase activator activity / p130Cas linkage to MAPK signaling for integrins / Receptor Mediated Mitophagy / interleukin-6-mediated signaling pathway / DNA biosynthetic process / EPHA-mediated growth cone collapse / positive regulation of Notch signaling pathway / Signaling by EGFR / stress fiber assembly / positive regulation of epithelial cell migration / positive regulation of smooth muscle cell migration / stimulatory C-type lectin receptor signaling pathway / cellular response to platelet-derived growth factor stimulus / regulation of cell-cell adhesion / dendritic growth cone / regulation of heart rate by cardiac conduction / RUNX2 regulates osteoblast differentiation / Recycling pathway of L1 / PECAM1 interactions / uterus development / GRB2:SOS provides linkage to MAPK signaling for Integrins / phospholipase binding / neurotrophin TRK receptor signaling pathway / negative regulation of telomere maintenance via telomerase / RHOU GTPase cycle / platelet-derived growth factor receptor signaling pathway / Long-term potentiation / negative regulation of anoikis / FCGR activation / RET signaling / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / positive regulation of bone resorption
Similarity search - Function
: / 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 / 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
Chem-0LI / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.49 Å
AuthorsSoriano-Maldonado, P. / Cuesta-Hernandez, H.N. / Plaza-Menacho, I.
Funding support Spain, 2items
OrganizationGrant numberCountry
Spanish Ministry of Science, Innovation, and UniversitiesBFU2017-86710-R Spain
Spanish Ministry of Science, Innovation, and UniversitiesRYC-2016-1938 Spain
Citation
Journal: Nat Commun / Year: 2023
Title: An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function.
Authors: Cuesta-Hernandez, H.N. / Contreras, J. / Soriano-Maldonado, P. / Sanchez-Wandelmer, J. / Yeung, W. / Martin-Hurtado, A. / Munoz, I.G. / Kannan, N. / Llimargas, M. / Munoz, J. / Plaza-Menacho, I.
#1: Journal: Biorxiv / Year: 2023
Title: Src Kinase Domain in complex with ponatinib
Authors: Soriano-Maldonado, p. / Cuesta-Hernandez, H.N. / Plaza-Menacho, I.
History
DepositionJun 10, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 22, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2023Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Mar 27, 2024Group: Database references / Category: citation / citation_author

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase Src
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,27915
Polymers67,1712
Non-polymers2,10813
Water1,47782
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6097
Polymers33,5851
Non-polymers1,0236
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6718
Polymers33,5851
Non-polymers1,0857
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.153, 124.631, 63.591
Angle α, β, γ (deg.)90.000, 90.150, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase Src / Proto-oncogene c-Src / pp60c-src / p60-Src


Mass: 33585.438 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: 6xH corresponds to the purification tag / Source: (gene. exp.) Homo sapiens (human) / Gene: SRC, SRC1 / Production host: Escherichia coli (E. coli)
References: UniProt: P12931, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0LI / 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide / Ponatinib


Mass: 532.559 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27F3N6O / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#3: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 2.51 Å3/Da / Density % sol: 51.08 % / Description: Thin needles
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: Tris 20 mM pH 8, 150 mM Sodium chloride, 1 mM DTT, 2-propanol and PEG 4.000
PH range: 7-8.5

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.615
11-h,-k,l20.385
ReflectionResolution: 2.49→63.59 Å / Num. obs: 21420 / % possible obs: 85.2 % / Redundancy: 2.5 % / CC1/2: 0.924 / Rmerge(I) obs: 0.18 / Rrim(I) all: 0.225 / Net I/σ(I): 5.1
Reflection shellResolution: 2.49→8.94 Å / Rmerge(I) obs: 0.041 / Num. unique obs: 20255

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3EL8

3el8


Resolution: 2.49→63.59 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.9 / SU B: 7.079 / SU ML: 0.169 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.123 / ESU R Free: 0.064 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2521 1164 5.4 %RANDOM
Rwork0.1751 ---
obs0.1793 20255 93.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 109.62 Å2 / Biso mean: 43.689 Å2 / Biso min: 16.59 Å2
Baniso -1Baniso -2Baniso -3
1--14.52 Å20 Å21.34 Å2
2--48.63 Å20 Å2
3----34.11 Å2
Refinement stepCycle: final / Resolution: 2.49→63.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4160 0 146 82 4388
Biso mean--47.14 36.09 -
Num. residues----518
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.024405
X-RAY DIFFRACTIONr_bond_other_d0.0020.024090
X-RAY DIFFRACTIONr_angle_refined_deg1.7572.0075961
X-RAY DIFFRACTIONr_angle_other_deg1.03639492
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1435514
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.77323.814194
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.59315744
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6481530
X-RAY DIFFRACTIONr_chiral_restr0.090.2639
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0214750
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02896
LS refinement shellResolution: 2.494→2.559 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 79 -
Rwork0.232 1378 -
all-1457 -
obs--86.67 %

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