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- PDB-5p9f: BTK IN COMPLEX WITH GDC-0834 -

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Basic information

Entry
Database: PDB / ID: 5p9f
TitleBTK IN COMPLEX WITH GDC-0834
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / LEAD OPTIMIZATION / PROTEIN KINASE
Function / homology
Function and homology information


regulation of B cell cytokine production / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / proteoglycan catabolic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / negative regulation of B cell activation / positive regulation of synoviocyte proliferation / neutrophil homeostasis ...regulation of B cell cytokine production / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / proteoglycan catabolic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / negative regulation of B cell activation / positive regulation of synoviocyte proliferation / neutrophil homeostasis / histamine secretion by mast cell / negative regulation of leukocyte proliferation / positive regulation of type I hypersensitivity / positive regulation of cGAS/STING signaling pathway / cellular response to molecule of fungal origin / MyD88 deficiency (TLR2/4) / IRAK4 deficiency (TLR2/4) / negative regulation of interleukin-10 production / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / MyD88-dependent toll-like receptor signaling pathway / phospholipase activator activity / positive regulation of immunoglobulin production / mesoderm development / Fc-epsilon receptor signaling pathway / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of NLRP3 inflammasome complex assembly / B cell activation / positive regulation of B cell proliferation / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / peptidyl-tyrosine phosphorylation / FCERI mediated Ca+2 mobilization / B cell receptor signaling pathway / positive regulation of phagocytosis / apoptotic signaling pathway / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calcium-mediated signaling / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / cellular response to reactive oxygen species / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / T cell receptor signaling pathway / positive regulation of tumor necrosis factor production / G beta:gamma signalling through BTK / DAP12 signaling / G alpha (12/13) signalling events / response to lipopolysaccharide / ER-Phagosome pathway / protein tyrosine kinase activity / cytoplasmic vesicle / Potential therapeutics for SARS / G alpha (q) signalling events / adaptive immune response / positive regulation of canonical NF-kappaB signal transduction / intracellular signal transduction / membrane raft / innate immune response / perinuclear region of cytoplasm / DNA-templated transcription / zinc ion binding / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase BTK, SH3 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 BTK, SH3 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 / 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 Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-2VL / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / molecular replacement / Resolution: 1.71 Å
AuthorsGardberg, A.S.
CitationJournal: Mol. Pharmacol. / Year: 2017
Title: Ability of Bruton's Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling.
Authors: Bender, A.T. / Gardberg, A. / Pereira, A. / Johnson, T. / Wu, Y. / Grenningloh, R. / Head, J. / Morandi, F. / Haselmayer, P. / Liu-Bujalski, L.
History
DepositionSep 20, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 24, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type
Revision 1.2Nov 17, 2021Group: Advisory / Database references ...Advisory / Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / entity / pdbx_deposit_group / pdbx_entity_nonpoly / pdbx_unobs_or_zero_occ_atoms
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_deposit_group.group_description / _pdbx_entity_nonpoly.name
Revision 1.3May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2637
Polymers32,3261
Non-polymers9376
Water5,152286
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.911, 103.931, 38.612
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Tyrosine-protein kinase BTK / Agammaglobulinemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK / Bruton tyrosine kinase


Mass: 32326.068 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): Hi5
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-2VL / N-{3-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl }-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide / GDC0834


Mass: 596.742 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H36N6O3S
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 286 / 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: 2.26 Å3/Da / Density % sol: 45.64 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7 / Details: PEG 3350, sodium actate, BisTrisPropane

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 12, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
211
ReflectionResolution: 1.71→59.66 Å / Num. obs: 32560 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 5.7 % / Biso Wilson estimate: 22.61 Å2 / Rmerge(I) obs: 0.108 / Net I/σ(I): 12.12
Reflection shellResolution: 1.71→1.96 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.525 / Mean I/σ(I) obs: 45.48 / % possible all: 99.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0005refinement
XSCALEdata scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: OTHER / Resolution: 1.71→59.66 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.926 / SU B: 5.501 / SU ML: 0.081 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.188 / ESU R Free: 0.117 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.223 2939 9.1 %RANDOM
Rwork0.15 ---
obs-29513 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 14.9 Å2
Baniso -1Baniso -2Baniso -3
1-0.28 Å20 Å20 Å2
2---0.38 Å20 Å2
3---0.1 Å2
Refinement stepCycle: LAST / Resolution: 1.71→59.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2182 0 65 286 2533
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222403
X-RAY DIFFRACTIONr_bond_other_d0.0020.022150
X-RAY DIFFRACTIONr_angle_refined_deg1.2751.9873262
X-RAY DIFFRACTIONr_angle_other_deg1.27535010
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0545296
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.1424.167108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.82215427
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4411513
X-RAY DIFFRACTIONr_chiral_restr0.0750.2341
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022720
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02503
X-RAY DIFFRACTIONr_nbd_refined0.1770.2475
X-RAY DIFFRACTIONr_nbd_other0.1620.22134
X-RAY DIFFRACTIONr_nbtor_refined0.1660.21210
X-RAY DIFFRACTIONr_nbtor_other0.0680.21215
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0870.2219
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0790.26
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2260.260
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0780.214
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.71→1.75 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.295 226 -
Rwork0.192 2165 -
obs--99.58 %

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