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- PDB-3t9t: Crystal structure of BTK mutant (F435T,K596R) complexed with Imid... -

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Basic information

Entry
Database: PDB / ID: 3t9t
TitleCrystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline
ComponentsTyrosine-protein kinase ITK/TSK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase domain / alpha/beta / ATP binding / phosphorylation / intracellular / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


gamma-delta T cell activation / NK T cell differentiation / activation of phospholipase C activity / Generation of second messenger molecules / cellular defense response / T cell activation / FCERI mediated Ca+2 mobilization / positive regulation of cytokine production / B cell receptor signaling pathway / non-specific protein-tyrosine kinase ...gamma-delta T cell activation / NK T cell differentiation / activation of phospholipase C activity / Generation of second messenger molecules / cellular defense response / T cell activation / FCERI mediated Ca+2 mobilization / positive regulation of cytokine production / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cell-cell junction / T cell receptor signaling pathway / adaptive immune response / intracellular signal transduction / phosphorylation / signal transduction / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase ITK, SH3 domain / Tyrosine-protein kinase ITK/TSK, catalytic domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain ...Tyrosine-protein kinase ITK, SH3 domain / Tyrosine-protein kinase ITK/TSK, catalytic domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology 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. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-IAQ / Tyrosine-protein kinase ITK/TSK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsHan, S. / Caspers, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis.
Authors: Kim, K.H. / Maderna, A. / Schnute, M.E. / Hegen, M. / Mohan, S. / Miyashiro, J. / Lin, L. / Li, E. / Keegan, S. / Lussier, J. / Wrocklage, C. / Nickerson-Nutter, C.L. / Wittwer, A.J. / ...Authors: Kim, K.H. / Maderna, A. / Schnute, M.E. / Hegen, M. / Mohan, S. / Miyashiro, J. / Lin, L. / Li, E. / Keegan, S. / Lussier, J. / Wrocklage, C. / Nickerson-Nutter, C.L. / Wittwer, A.J. / Soutter, H. / Caspers, N. / Han, S. / Kurumbail, R. / Dunussi-Joannopoulos, K. / Douhan, J. / Wissner, A.
History
DepositionAug 3, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2011Provider: repository / Type: Initial release
Revision 1.1Oct 26, 2011Group: Database references
Revision 1.2Mar 6, 2024Group: 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 / software / 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 / _software.name / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase ITK/TSK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,0754
Polymers30,4591
Non-polymers6173
Water2,054114
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.340, 69.350, 47.270
Angle α, β, γ (deg.)90.00, 115.70, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein kinase ITK/TSK / BTK / Bruton's Tyrosine Kinase / Kinase EMT / T-cell-specific kinase / Tyrosine-protein kinase Lyk


Mass: 30458.809 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 354-620) / Mutation: F435T,K596R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITK, EMT, LYK
References: UniProt: Q08881, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-IAQ / (2Z)-4-(dimethylamino)-N-{7-fluoro-4-[(2-methylphenyl)amino]imidazo[1,5-a]quinoxalin-8-yl}-N-methylbut-2-enamide


Mass: 432.493 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H25FN6O
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 114 / Source method: isolated from a natural source / Formula: H2O

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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: 2.25 Å3/Da / Density % sol: 45.26 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 14% PEG3350, 0.1 M magnesium acetate, 0.1 M HEPES, pH 7.2, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 21, 2010
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→34.675 Å / Num. obs: 32146 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 1.65→1.69 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.551 / Mean I/σ(I) obs: 2.1 / Num. unique all: 2356 / % possible all: 98.9

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Processing

Software
NameVersionClassification
autoPROCdata collection
PHASERphasing
REFMAC5.4.0069refinement
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→34.67 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.947 / SU B: 4.303 / SU ML: 0.066 / Cross valid method: THROUGHOUT / ESU R: 0.135 / ESU R Free: 0.094 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20457 1626 5.1 %RANDOM
Rwork0.1666 ---
obs0.16851 30493 100 %-
all-32146 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 17.881 Å2
Baniso -1Baniso -2Baniso -3
1--0.9 Å20 Å2-0.69 Å2
2---0.69 Å20 Å2
3---0.99 Å2
Refinement stepCycle: LAST / Resolution: 1.65→34.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2110 0 44 114 2268
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222235
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.291.9713027
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2045268
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.89923.714105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.51715380
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.631515
X-RAY DIFFRACTIONr_chiral_restr0.1110.2320
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211709
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_it2.2441.51325
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.97922143
X-RAY DIFFRACTIONr_scbond_it4.4283910
X-RAY DIFFRACTIONr_scangle_it6.0414.5884
X-RAY DIFFRACTIONr_rigid_bond_restr3.34232235
X-RAY DIFFRACTIONr_sphericity_free5.3283114
X-RAY DIFFRACTIONr_sphericity_bonded3.04332181
LS refinement shellResolution: 1.65→1.693 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.235 115 -
Rwork0.199 2231 -
obs--100 %

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