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- PDB-4lud: Crystal Structure of HCK in complex with the fluorescent compound... -

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Basic information

Entry
Database: PDB / ID: 4lud
TitleCrystal Structure of HCK in complex with the fluorescent compound SKF86002
ComponentsTyrosine-protein kinase HCK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / cocrystallization / SKF86002 / fluorescence / inhibitor screening / kinase / 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 / SH2 domain / SHC Adaptor Protein / SH3 Domains / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain ...Tyrosine-protein kinase HCK, SH2 domain / SH2 domain / SHC Adaptor Protein / SH3 Domains / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH3 type barrels. / 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 / Roll / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-SK8 / Tyrosine-protein kinase HCK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.85 Å
AuthorsParker, L.J. / Tanaka, A. / Handa, N. / Honda, K. / Tomabechi, Y. / Shirouzu, M. / Yokoyama, S.
CitationJournal: Acta Crystallogr.,Sect.D / Year: 2014
Title: Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002.
Authors: Parker, L.J. / Taruya, S. / Tsuganezawa, K. / Ogawa, N. / Mikuni, J. / Honda, K. / Tomabechi, Y. / Handa, N. / Shirouzu, M. / Yokoyama, S. / Tanaka, A.
History
DepositionJul 25, 2013Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Feb 12, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / struct_conn / struct_ref_seq_dif
Item: _citation.country / _citation.journal_id_CSD ..._citation.country / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details
Revision 1.2Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ncs_dom_lim / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase HCK
B: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,06312
Polymers104,0002
Non-polymers1,06210
Water1,40578
1
A: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,5056
Polymers52,0001
Non-polymers5055
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,5576
Polymers52,0001
Non-polymers5575
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.300, 73.400, 180.290
Angle α, β, γ (deg.)90.00, 96.77, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain: (Details: chain B) / NCS domain segments: (Selection details: chain 'B')

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Components

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Protein , 1 types, 2 molecules AB

#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.: 2 / Fragment: UNP residues 81-526 / Mutation: Q502E/Q503E/Q504I
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

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Non-polymers , 5 types, 88 molecules

#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-SK8 / 6-(4-fluorophenyl)-5-(pyridin-4-yl)-2,3-dihydroimidazo[2,1-b][1,3]thiazole / SKF-86002


Mass: 297.350 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H12FN3S
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 78 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.05 Å3/Da / Density % sol: 59.69 % / Mosaicity: 0.48 °
Crystal growTemperature: 288 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M Tris, 0.1M Calcium Acetate, 20% Glycerol, 24% PEG 6000, 2mM SKF86002, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 288K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL26B2 / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Feb 1, 2013
Details: Fixed exit Si double crystal monochromator followed by a two dimensional focusing mirror
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.85→179.033 Å / Num. all: 29538 / Num. obs: 29538 / % possible obs: 100 % / Redundancy: 3.8 % / Biso Wilson estimate: 57.82 Å2 / Rsym value: 0.082 / Net I/σ(I): 10.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) allRmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.85-33.80.4760.4091.91636542740.2420.4760.4093.4100
3-3.193.80.2780.2393.11552740570.1420.2780.2395.1100
3.19-3.413.80.1810.1554.81458738040.0920.1810.1556.9100
3.41-3.683.80.1110.0957.51368535750.0560.1110.0959.6100
3.68-4.033.80.0820.079.91255532840.0420.0820.0712.3100
4.03-4.513.80.0660.05610.31127929480.0340.0660.05615.1100
4.51-5.23.80.1050.095.91002826240.0530.1050.0916100
5.2-6.373.80.1140.0985.6848122330.0580.1140.09815.8100
6.37-9.013.80.0420.03615.8658217550.0220.0420.03617.4100
9.01-47.7583.60.0360.03113.935119840.0190.0360.03119.199.3

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.04 Å47.76 Å
Translation6.04 Å47.76 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASER2.5.2phasing
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.11data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2C0T

2c0t


Resolution: 2.85→47.758 Å / Occupancy max: 1 / Occupancy min: 0.8 / FOM work R set: 0.759 / SU ML: 0.45 / σ(F): 1.39 / Phase error: 30.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2607 1499 5.08 %
Rwork0.2123 --
obs0.2149 29497 99.89 %
all-30996 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 188.82 Å2 / Biso mean: 70.803 Å2 / Biso min: 20.74 Å2
Refinement stepCycle: LAST / Resolution: 2.85→47.758 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6606 0 65 78 6749
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0026823
X-RAY DIFFRACTIONf_angle_d0.6229228
X-RAY DIFFRACTIONf_chiral_restr0.025988
X-RAY DIFFRACTIONf_plane_restr0.0041170
X-RAY DIFFRACTIONf_dihedral_angle_d12.1772536
Refine LS restraints NCSNumber: 3670 / Type: POSITIONAL / Rms dev position: 7.538 Å
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.85-2.9420.36731380.293725142652
2.942-3.04720.36431450.278125312676
3.0472-3.16910.33041220.264225002622
3.1691-3.31330.28081490.243225192668
3.3133-3.4880.28541240.2125812705
3.488-3.70640.26051270.202825342661
3.7064-3.99250.22671420.193925282670
3.9925-4.3940.21941360.167225662702
4.394-5.02920.22651270.1725222649
5.0292-6.3340.25711450.222925702715
6.334-47.76480.25841440.232726332777
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)
11.13080.14240.67561.5761-2.31734.7490.02360.0240.06220.1283-0.20950.03210.23710.21740.18091.06990.00380.05510.36720.00370.407517.1774-27.677475.3033
25.183-1.122-1.25895.4430.67316.2422-0.04560.2229-0.055-0.47040.2467-0.45380.26810.5799-0.13810.46240.05410.0180.33380.01760.347428.3621-19.238652.3495
30.31170.3564-1.39481.2277-0.76696.511-0.06750.0930.14130.3848-0.06720.2007-0.1262-0.48190.10910.76370.05360.01910.4264-0.05240.38559.5293-2.107376.0428
42.3356-0.1349-1.07054.05581.01873.82980.1477-0.03610.3888-0.0582-0.33270.4308-0.7152-0.65240.19030.84940.0786-0.13070.5588-0.04470.381310.21927.556856.1811
52.6479-0.09250.25923.7105-0.46771.6003-0.2080.0198-0.18760.6632-0.1453-0.2417-0.37780.09380.30331.2827-0.0543-0.17190.37360.04860.46035.472323.8119.8486
62.62011.47380.70074.5202-0.68713.8374-0.52050.72630.0329-0.38450.114-0.661-1.77351.41260.2980.965-0.258-0.0930.78430.16760.524224.16313.012928.0678
72.2569-0.22612.54132.5640.30496.1817-0.2472-0.16240.1888-0.4221-0.12130.312-0.3243-0.47120.28610.36940.0269-0.0250.322-0.04250.35380.7178-3.189615.5837
80.3356-0.1132-0.94510.76130.26832.683-0.2279-0.07850.0141-0.22040.00670.92280.1878-0.8250.0730.2507-0.16110.08540.7118-0.12920.6063-6.1275-15.312428.5845
92.19381.14261.1294.6974-0.06164.32210.1465-0.2466-0.19390.4338-0.13820.0710.7234-0.3557-0.00070.5253-0.02960.04110.38960.02870.2569.3671-14.28435.6503
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 85:154)A85 - 154
2X-RAY DIFFRACTION2chain 'A' and (resseq 156:251)A156 - 251
3X-RAY DIFFRACTION3chain 'A' and (resseq 252:379)A252 - 379
4X-RAY DIFFRACTION4chain 'A' and (resseq 380:531)A380 - 531
5X-RAY DIFFRACTION5chain 'B' and (resseq 85:140)B85 - 140
6X-RAY DIFFRACTION6chain 'B' and (resseq 141:250)B141 - 250
7X-RAY DIFFRACTION7chain 'B' and (resseq 251:402)B251 - 402
8X-RAY DIFFRACTION8chain 'B' and (resseq 403:440)B403 - 440
9X-RAY DIFFRACTION9chain 'B' and (resseq 441:529)B441 - 529

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