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- PDB-8xkp: Crystal structure of human tyrosine-protein kinase Fes/Fps in com... -

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Basic information

Entry
Database: PDB / ID: 8xkp
TitleCrystal structure of human tyrosine-protein kinase Fes/Fps in complex with compound 17c
ComponentsTyrosine-protein kinase Fes/Fps
KeywordsTRANSFERASE / FES / c-Fes / tyrosine protein kinase
Function / homology
Function and homology information


positive regulation of myeloid cell differentiation / regulation of mast cell degranulation / regulation of vesicle-mediated transport / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / cellular response to vitamin D / regulation of cell motility / CRMPs in Sema3A signaling / microtubule bundle formation / positive regulation of monocyte differentiation / centrosome cycle ...positive regulation of myeloid cell differentiation / regulation of mast cell degranulation / regulation of vesicle-mediated transport / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / cellular response to vitamin D / regulation of cell motility / CRMPs in Sema3A signaling / microtubule bundle formation / positive regulation of monocyte differentiation / centrosome cycle / myoblast proliferation / immunoglobulin receptor binding / cardiac muscle cell proliferation / regulation of cell differentiation / Sema3A PAK dependent Axon repulsion / regulation of cell adhesion / positive regulation of microtubule polymerization / phosphatidylinositol binding / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / Signaling by SCF-KIT / peptidyl-tyrosine phosphorylation / positive regulation of neuron projection development / cytoplasmic side of plasma membrane / chemotaxis / regulation of cell shape / regulation of cell population proliferation / microtubule cytoskeleton / protein autophosphorylation / microtubule binding / protein tyrosine kinase activity / cytoplasmic vesicle / cell adhesion / focal adhesion / Golgi apparatus / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase, Fes/Fps type / Fes/Fps/Fer, SH2 domain / Fes/CIP4, and EFC/F-BAR homology domain / Fes/CIP4 homology domain / FCH domain / F-BAR domain / F-BAR domain profile. / AH/BAR domain superfamily / : / SH2 domain ...Tyrosine-protein kinase, Fes/Fps type / Fes/Fps/Fer, SH2 domain / Fes/CIP4, and EFC/F-BAR homology domain / Fes/CIP4 homology domain / FCH domain / F-BAR domain / F-BAR domain profile. / AH/BAR domain superfamily / : / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / 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 Fes/Fps
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsBaba, D. / Hanzawa, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Optimization of Novel Pyrido-pyridazinone Derivatives as FER Tyrosine Kinase Inhibitors, Leading to the Potent DS08701581.
Authors: Taniguchi, T. / Yasumatsu, I. / Inagaki, H. / Baba, D. / Toyota, A. / Kaneta, Y. / Odagiri, T. / Momose, T. / Kawai, J. / Imaoka, T. / Nakayama, K.
History
DepositionDec 23, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase Fes/Fps
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1654
Polymers42,4851
Non-polymers6813
Water2,144119
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area450 Å2
ΔGint-35 kcal/mol
Surface area17970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.651, 80.651, 131.207
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

#1: Protein Tyrosine-protein kinase Fes/Fps / Feline sarcoma/Fujinami avian sarcoma oncogene homolog / Proto-oncogene c-Fes / Proto-oncogene c- ...Feline sarcoma/Fujinami avian sarcoma oncogene homolog / Proto-oncogene c-Fes / Proto-oncogene c-Fps / p93c-fes


Mass: 42484.652 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FES, FPS / Production host: Escherichia coli (E. coli)
References: UniProt: P07332, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-A1LWS / 7-[[(1R,2S)-2-azanylcyclohexyl]amino]-5-[[3-[(2S,6R)-2,6-dimethylmorpholin-4-yl]phenyl]amino]-4-oxidanylidene-3H-pyrido[3,4-d]pyridazine-8-carbonitrile


Mass: 488.585 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H32N8O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.9 Å3/Da / Density % sol: 57.58 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7
Details: 0.1M Bis-Tris propane, 0.2M sodium sulfate, 15% PEG 3350, 10% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 30289 / % possible obs: 99.9 % / Redundancy: 7.6 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 26.58
Reflection shellResolution: 2.05→2.09 Å / Rmerge(I) obs: 0.461 / Num. unique obs: 1507 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.05→30 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.939 / SU B: 7.651 / SU ML: 0.107 / Cross valid method: THROUGHOUT / ESU R: 0.172 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.23386 1457 4.8 %RANDOM
Rwork0.18967 ---
obs0.19169 28807 99.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 27.316 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20.02 Å20 Å2
2--0.04 Å20 Å2
3----0.05 Å2
Refinement stepCycle: 1 / Resolution: 2.05→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2946 0 46 119 3111
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0193063
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3841.9854156
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2395371
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.97523.406138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.84815518
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5671524
X-RAY DIFFRACTIONr_chiral_restr0.0860.2450
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212353
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.05→2.103 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 109 -
Rwork0.242 2057 -
obs--99.72 %

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