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- PDB-3vs2: Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhi... -

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Basic information

Entry
Database: PDB / ID: 3vs2
TitleCrystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 7-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
ComponentsTyrosine-protein kinase HCK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / tyrosine kinase / SRC-family / 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 / lysosome / protein phosphorylation / 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-VSB / Tyrosine-protein kinase HCK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.609 Å
AuthorsKuratani, M. / Tomabechi, Y. / Niwa, H. / Parker, J.L. / Handa, N. / Yokoyama, S.
CitationJournal: Sci Transl Med / Year: 2013
Title: A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo
Authors: Saito, Y. / Yuki, H. / Kuratani, M. / Hashizume, Y. / Takagi, S. / Honma, T. / Tanaka, A. / Shirouzu, M. / Mikuni, J. / Handa, N. / Ogahara, I. / Sone, A. / Najima, Y. / Tomabechi, Y. / ...Authors: Saito, Y. / Yuki, H. / Kuratani, M. / Hashizume, Y. / Takagi, S. / Honma, T. / Tanaka, A. / Shirouzu, M. / Mikuni, J. / Handa, N. / Ogahara, I. / Sone, A. / Najima, Y. / Tomabechi, Y. / Wakiyama, M. / Uchida, N. / Tomizawa-Murasawa, M. / Kaneko, A. / Tanaka, S. / Suzuki, N. / Kajita, H. / Aoki, Y. / Ohara, O. / Shultz, L.D. / Fukami, T. / Goto, T. / Taniguchi, S. / Yokoyama, S. / Ishikawa, F.
History
DepositionApr 21, 2012Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 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_ref_seq_dif / 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.pdbx_leaving_atom_flag / _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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.2Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.3Oct 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)105,1178
Polymers104,0002
Non-polymers1,1166
Water2,198122
1
A: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,5584
Polymers52,0001
Non-polymers5583
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase HCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,5584
Polymers52,0001
Non-polymers5583
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.510, 73.090, 180.960
Angle α, β, γ (deg.)90.00, 96.26, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 2 / Fragment: UNP residues 81-526 / Mutation: Q528E, Q529E, Q530I
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-VSB / 7-[cis-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
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 122 / 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: 3.07 Å3/Da / Density % sol: 59.89 %
Crystal growTemperature: 288 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M Tris, 0.1M calcium acetate, 20% glycerol, 21% PEG6000, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 288K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 15, 2011
RadiationMonochromator: Si / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.609→50 Å / Num. all: 38625 / Num. obs: 38046 / % possible obs: 98.5 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Biso Wilson estimate: 62.84 Å2
Reflection shellResolution: 2.61→2.76 Å / % possible all: 94.1

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3VRY

3vry


Resolution: 2.609→40.691 Å / Occupancy max: 1 / Occupancy min: 0.79 / SU ML: 0.47 / σ(F): 1.99 / Phase error: 33.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2785 1901 5 %random
Rwork0.2257 ---
all0.2785 38046 --
obs0.2284 38012 98.43 %-
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 68.437 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso max: 148.95 Å2 / Biso mean: 76.3176 Å2 / Biso min: 26.9 Å2
Baniso -1Baniso -2Baniso -3
1-34.0132 Å2-0 Å2-10.4485 Å2
2---14.3336 Å2-0 Å2
3----19.6796 Å2
Refinement stepCycle: LAST / Resolution: 2.609→40.691 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6991 0 76 122 7189
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077240
X-RAY DIFFRACTIONf_angle_d1.7559786
X-RAY DIFFRACTIONf_chiral_restr0.0521037
X-RAY DIFFRACTIONf_plane_restr0.0041238
X-RAY DIFFRACTIONf_dihedral_angle_d13.7472744
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 (%)
2.6086-2.67390.44291200.38642273239388
2.6739-2.74610.4691360.37232576271299
2.7461-2.82690.3881370.33462590272799
2.8269-2.91820.3871360.3092585272199
2.9182-3.02240.33771380.27532627276599
3.0224-3.14340.34181320.24532523265599
3.1434-3.28640.32671370.242726132750100
3.2864-3.45960.30961370.22742607274499
3.4596-3.67620.29731360.21832588272499
3.6762-3.95980.24631360.21082570270699
3.9598-4.35790.24051380.1852618275699
4.3579-4.98750.19951370.173826122749100
4.9875-6.280.32681400.241526532793100
6.28-40.69550.22411410.20942676281799

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