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- PDB-5h0b: Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhi... -

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Basic information

Entry
Database: PDB / ID: 5h0b
TitleCrystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor (S)-2-(((1r,4S)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)amino)-4-methylpentanoic acid
ComponentsTyrosine-protein kinase HCK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


leukocyte degranulation / innate immune response-activating signaling pathway / leukocyte migration involved in immune response / respiratory burst after phagocytosis / regulation of podosome assembly / FLT3 signaling through SRC family kinases / regulation of phagocytosis / regulation of DNA-binding transcription factor activity / Nef and signal transduction / positive regulation of actin filament polymerization ...leukocyte degranulation / innate immune response-activating signaling pathway / leukocyte migration involved in immune response / respiratory burst after phagocytosis / regulation of podosome assembly / FLT3 signaling through SRC family kinases / regulation of phagocytosis / regulation of DNA-binding transcription factor activity / Nef and signal transduction / positive regulation of actin filament polymerization / Fc-gamma receptor signaling pathway involved in phagocytosis / mesoderm development / FCGR activation / type II interferon-mediated signaling pathway / transport vesicle / Signaling by CSF3 (G-CSF) / phosphotyrosine residue binding / FCGR3A-mediated IL10 synthesis / cell surface receptor protein tyrosine kinase signaling pathway / lipopolysaccharide-mediated signaling pathway / peptidyl-tyrosine phosphorylation / integrin-mediated signaling pathway / cell projection / regulation of actin cytoskeleton organization / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / Regulation of signaling by CBL / non-specific protein-tyrosine kinase / negative regulation of inflammatory response to antigenic stimulus / Inactivation of CSF3 (G-CSF) signaling / caveola / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / regulation of cell shape / protein autophosphorylation / regulation of inflammatory response / protein tyrosine kinase activity / cell differentiation / cytoskeleton / protein phosphorylation / lysosome / cell adhesion / defense response to Gram-positive bacterium / intracellular signal transduction / inflammatory response / signaling receptor binding / focal adhesion / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / lipid binding / negative regulation of apoptotic process / Golgi apparatus / ATP binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase HCK, 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 ...Tyrosine-protein kinase HCK, 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
Chem-OOQ / Tyrosine-protein kinase HCK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.651 Å
AuthorsTomabechi, Y. / Kukimoto-Niino, M. / Shirouzu, M.
CitationJournal: Bioorg. Med. Chem. / Year: 2017
Title: Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen.
Authors: Yuki, H. / Kikuzato, K. / Koda, Y. / Mikuni, J. / Tomabechi, Y. / Kukimoto-Niino, M. / Tanaka, A. / Shirai, F. / Shirouzu, M. / Koyama, H. / Honma, T.
History
DepositionOct 4, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 11, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,5142
Polymers52,0001
Non-polymers5141
Water6,882382
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.177, 85.578, 130.277
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Tyrosine-protein kinase HCK / Hematopoietic cell kinase / Hemopoietic cell kinase / p59-HCK/p60-HCK / p59Hck / p61Hck


Mass: 52000.227 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 81-526 / Mutation: Q523E, Q524E, Q525I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HCK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08631, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-OOQ / (2~{S})-2-[[4-[4-azanyl-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]azaniumyl]-4-methyl-pentanoate


Mass: 513.631 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H35N5O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 382 / Source method: isolated from a natural source / Formula: H2O
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: 2.34 Å3/Da / Density % sol: 47.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.22-0.25 M ammonium formate, 12-22 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32XU / Wavelength: 1 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Dec 17, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→50 Å / Num. obs: 57527 / % possible obs: 98.9 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.075 / Rpim(I) all: 0.031 / Rrim(I) all: 0.081 / Χ2: 2.168 / Net I/av σ(I): 44.504 / Net I/σ(I): 11.5 / Num. measured all: 395904
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.65-1.6850.477191.1
1.68-1.715.70.443195
1.71-1.746.40.413197.9
1.74-1.7870.3541100
1.78-1.827.20.309199
1.82-1.867.20.2651100
1.86-1.97.20.222199.2
1.9-1.967.20.195199.5
1.96-2.017.20.1661100
2.01-2.087.20.143199.6
2.08-2.157.20.132199.8
2.15-2.247.20.1181100
2.24-2.347.20.107199.9
2.34-2.467.20.098199.9
2.46-2.627.20.089199.9
2.62-2.827.10.081199.9
2.82-3.1170.073199.9
3.11-3.556.90.066199.9
3.55-4.486.80.058199.9
4.48-506.40.048197

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation1.65 Å38.73 Å
Translation1.65 Å38.73 Å

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Processing

Software
NameVersionClassification
DENZOdata collection
HKL-2000data scaling
PHASER2.5.5phasing
PHENIX1.9_1690refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3VS3

3vs3


Resolution: 1.651→38.725 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.56
RfactorNum. reflection% reflection
Rfree0.2049 2000 3.48 %
Rwork0.1802 --
obs0.181 57461 97.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 152.82 Å2 / Biso mean: 38.4663 Å2 / Biso min: 13.84 Å2
Refinement stepCycle: final / Resolution: 1.651→38.725 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3613 0 38 382 4033
Biso mean--22.94 40.35 -
Num. residues----447
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073742
X-RAY DIFFRACTIONf_angle_d1.0285059
X-RAY DIFFRACTIONf_chiral_restr0.043535
X-RAY DIFFRACTIONf_plane_restr0.005645
X-RAY DIFFRACTIONf_dihedral_angle_d12.8371416
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6513-1.69260.30221070.2322953306075
1.6926-1.73830.23471390.223866400596
1.7383-1.78950.22941450.208139994144100
1.7895-1.84720.25121420.20143956409899
1.8472-1.91330.20711440.19334001414599
1.9133-1.98990.22761450.191240114156100
1.9899-2.08040.2331440.188240164160100
2.0804-2.19010.22311460.181740244170100
2.1901-2.32730.21751460.183840404186100
2.3273-2.5070.17661450.184140544199100
2.507-2.75920.23221470.187640624209100
2.7592-3.15830.21731480.182640914239100
3.1583-3.97850.19981490.166241464295100
3.9785-38.73580.17091530.16914242439598

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