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- PDB-4lue: Crystal Structure of HCK in complex with 7-[trans-4-(4-methylpipe... -

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Entry
Database: PDB / ID: 4lue
TitleCrystal Structure of HCK in complex with 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (resulting from displacement of 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 / respiratory burst after phagocytosis / leukocyte migration involved in immune response / regulation of podosome assembly / FLT3 signaling through SRC family kinases / regulation of phagocytosis / Nef and signal transduction / regulation of DNA-binding transcription factor activity / positive regulation of actin filament polymerization ...leukocyte degranulation / innate immune response-activating signaling pathway / respiratory burst after phagocytosis / leukocyte migration involved in immune response / regulation of podosome assembly / FLT3 signaling through SRC family kinases / regulation of phagocytosis / Nef and signal transduction / regulation of DNA-binding transcription factor activity / positive regulation of actin filament polymerization / Fc-gamma receptor signaling pathway involved in phagocytosis / mesoderm development / FCGR activation / type II interferon-mediated signaling pathway / Signaling by CSF3 (G-CSF) / transport vesicle / phosphotyrosine residue binding / FCGR3A-mediated IL10 synthesis / lipopolysaccharide-mediated signaling pathway / cell surface receptor protein tyrosine kinase signaling pathway / integrin-mediated signaling pathway / cell projection / non-membrane spanning protein tyrosine kinase activity / regulation of actin cytoskeleton organization / FCGR3A-mediated phagocytosis / Regulation of signaling by CBL / non-specific protein-tyrosine kinase / negative regulation of inflammatory response to antigenic stimulus / cytokine-mediated signaling pathway / Inactivation of CSF3 (G-CSF) signaling / peptidyl-tyrosine phosphorylation / caveola / cytoplasmic side of plasma membrane / 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 / lysosome / cell adhesion / intracellular signal transduction / protein phosphorylation / 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 / SH2 domain superfamily / Src homology 3 domains / SH3 type barrels. / 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
IMIDAZOLE / Chem-VSE / Tyrosine-protein kinase HCK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.04 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_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_asym_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_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 1.4Nov 6, 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)105,55413
Polymers104,0002
Non-polymers1,55411
Water27015
1
A: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7436
Polymers52,0001
Non-polymers7425
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,8127
Polymers52,0001
Non-polymers8116
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.400, 93.530, 181.490
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
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 , 6 types, 26 molecules

#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-VSE / 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 482.620 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H34N6O
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 15 / 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 Å3/Da / Density % sol: 58.93 % / Mosaicity: 0.56 °
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, soaked with 2mM inhibitor in DMSO., 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: 3.04→90.745 Å / Num. all: 24812 / Num. obs: 24812 / % possible obs: 100 % / Redundancy: 7 % / Biso Wilson estimate: 54.36 Å2 / Rsym value: 0.108 / Net I/σ(I): 12.5
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
3.04-3.26.90.4050.3741.92448835490.1530.4050.3745100
3.2-3.46.90.2890.2672.62335233670.1090.2890.2676.6100
3.4-3.636.90.1970.1823.42193931850.0750.1970.1829.3100
3.63-3.926.90.1440.1334.62048629630.0550.1440.13311.9100
3.92-4.37.10.0850.0798.61948827300.0320.0850.07915.7100
4.3-4.817.20.0750.079.21808024960.0280.0750.0718100
4.81-5.557.30.1040.0976.21621822260.0380.1040.09716.9100
5.55-6.87.20.1360.1264.21370719020.050.1360.12616.3100
6.8-9.6170.0480.04412.51056215020.0180.0480.04420.1100
9.61-57.0686.40.0370.03414.757298920.0140.0370.03422.399.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation4.06 Å55.02 Å
Translation4.06 Å55.02 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: 3VS3

3vs3


Resolution: 3.04→46.765 Å / Occupancy max: 1 / Occupancy min: 0.82 / FOM work R set: 0.7686 / SU ML: 0.34 / σ(F): 1.37 / Phase error: 28.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2562 1259 5.09 %transferred from model
Rwork0.2054 ---
obs0.208 24715 99.81 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 162.09 Å2 / Biso mean: 71.5949 Å2 / Biso min: 24 Å2
Refinement stepCycle: LAST / Resolution: 3.04→46.765 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6694 0 105 15 6814
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0036959
X-RAY DIFFRACTIONf_angle_d0.6469413
X-RAY DIFFRACTIONf_chiral_restr0.0271010
X-RAY DIFFRACTIONf_plane_restr0.0041183
X-RAY DIFFRACTIONf_dihedral_angle_d14.3592619
Refine LS restraints NCSNumber: 3763 / Type: POSITIONAL / Rms dev position: 7.616 Å
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
3.04-3.16170.291160.243725612677
3.1617-3.30560.34681360.238225672703
3.3056-3.47980.28211490.218725712720
3.4798-3.69770.24131390.208125642703
3.6977-3.98310.23851440.201925702714
3.9831-4.38360.2491440.170825912735
4.3836-5.01730.21891560.162526032759
5.0173-6.31880.23181430.216226452788
6.3188-46.77050.28391320.23327842916
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)
12.5877-1.7616-2.50792.62682.3065.87020.02690.14480.0384-0.2124-0.3290.11870.0143-0.73110.34020.41820.00850.02030.902-0.16450.508311.5994-6.8537-16.9612
26.48080.74711.51564.6611.2795.33880.3680.2887-0.6784-0.123-0.2920.02220.2367-0.1078-0.15690.4478-0.00310.04310.4466-0.08570.417820.3262-20.8302-37.3688
32.44080.04630.31671.19311.32643.7224-0.128-0.00260.2807-0.146-0.00910.0018-0.19130.17780.12250.4324-0.03-0.0230.31970.03940.394943.0848-1.0051-27.9914
42.05161.7473-2.15293.6069-2.51675.80830.11580.04650.08030.2159-0.4113-0.0120.14530.70750.34210.45410.06050.0370.95310.09290.480861.7142-5.6214-80.4647
56.8231-0.21160.64726.60350.43435.85150.2612-0.1949-0.57850.5175-0.1894-0.0630.70461.4575-0.04580.65250.19550.09730.83050.06430.464152.807-21.2099-59.3041
61.95550.1960.01241.8091-2.13985.1437-0.01350.13720.26360.26550.02370.1359-0.4552-0.4085-0.01580.42560.027-0.01090.4409-0.0350.423531.2175-0.7046-69.6536
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 85:155)A85 - 181
2X-RAY DIFFRACTION2chain 'A' and (resseq 156:252)A156 - 278
3X-RAY DIFFRACTION3chain 'A' and (resseq 253:530)A253 - 530
4X-RAY DIFFRACTION4chain 'B' and (resseq 85:155)B85 - 181
5X-RAY DIFFRACTION5chain 'B' and (resseq 156:242)B156 - 268
6X-RAY DIFFRACTION6chain 'B' and (resseq 243:530)B243 - 530

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