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- PDB-5fbo: BTK-inhibitor co-structure -

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Basic information

Entry
Database: PDB / ID: 5fbo
TitleBTK-inhibitor co-structure
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE inhibitor / KINASE / PHOSPHATASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell ...regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / cellular response to interleukin-7 / MyD88 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / positive regulation of immunoglobulin production / positive regulation of NLRP3 inflammasome complex assembly / negative regulation of interleukin-10 production / phospholipase activator activity / B cell activation / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / RHO GTPases Activate WASPs and WAVEs / positive regulation of phagocytosis / positive regulation of B cell proliferation / cell maturation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calcium-mediated signaling / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / G beta:gamma signalling through BTK / Regulation of actin dynamics for phagocytic cup formation / cellular response to reactive oxygen species / peptidyl-tyrosine phosphorylation / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / G alpha (12/13) signalling events / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / G alpha (q) signalling events / protein tyrosine kinase activity / adaptive immune response / Potential therapeutics for SARS / response to lipopolysaccharide / intracellular signal transduction / membrane raft / protein phosphorylation / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / metal ion 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 / SH3 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 / 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-5WE / Chem-5WH / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.894 Å
AuthorsFischmann, T.O.
CitationJournal: ACS Med Chem Lett / Year: 2016
Title: Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.
Authors: Liu, J. / Guiadeen, D. / Krikorian, A. / Gao, X. / Wang, J. / Boga, S.B. / Alhassan, A.B. / Yu, Y. / Vaccaro, H. / Liu, S. / Yang, C. / Wu, H. / Cooper, A. / de Man, J. / Kaptein, A. / ...Authors: Liu, J. / Guiadeen, D. / Krikorian, A. / Gao, X. / Wang, J. / Boga, S.B. / Alhassan, A.B. / Yu, Y. / Vaccaro, H. / Liu, S. / Yang, C. / Wu, H. / Cooper, A. / de Man, J. / Kaptein, A. / Maloney, K. / Hornak, V. / Gao, Y.D. / Fischmann, T.O. / Raaijmakers, H. / Vu-Pham, D. / Presland, J. / Mansueto, M. / Xu, Z. / Leccese, E. / Zhang-Hoover, J. / Knemeyer, I. / Garlisi, C.G. / Bays, N. / Stivers, P. / Brandish, P.E. / Hicks, A. / Kim, R. / Kozlowski, J.A.
History
DepositionDec 14, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Derived calculations / Refinement description / Category: pdbx_struct_oper_list / software
Item: _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.2Apr 18, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.page_last ..._citation.journal_abbrev / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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)32,6983
Polymers31,5981
Non-polymers1,1002
Water1,54986
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.390, 104.470, 38.080
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: 31598.287 Da / Num. of mol.: 1 / Fragment: Protein kinase domain (UNP residues 389-659)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Cell line (production host): SF21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-5WH / 4-[8-azanyl-3-[(3~{R},6~{S})-1-cyclopropylcarbonyl-6-methyl-piperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl]-3-fluoranyl-~{N}-[4-(trifluoromethyl)pyridin-2-yl]benzamide


Mass: 581.564 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C29H27F4N7O2 / References: non-specific protein-tyrosine kinase
#3: Chemical ChemComp-5WE / 4-[8-azanyl-3-[(2~{S})-1-[4-(dimethylamino)butanoyl]pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-~{N}-(1,3-thiazol-2-yl)benzamide


Mass: 518.634 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N8O2S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 2.28 Å3/Da / Density % sol: 46.08 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 5.5 v/v PEG 10000, 0.1M Ammonium Acetate, 0.1M Bis-Tris Cl pH 6.5, 2.5 mM(S)-4-(8-amino-3-(1-(4-(dimethylamino)butanoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(thiazol-2-yl)benzamide
PH range: 5.0-6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.894→38.1 Å / Num. obs: 23720 / % possible obs: 100 % / Redundancy: 6.2 % / Biso Wilson estimate: 34.15 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 18.2
Reflection shellResolution: 1.894→1.9 Å / Redundancy: 6 % / Rmerge(I) obs: 0.635 / Mean I/σ(I) obs: 2.7 / % possible all: 99.6

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
autoPROCdata scaling
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: in-house structure

Resolution: 1.894→38.08 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.238 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.157 / SU Rfree Blow DPI: 0.137 / SU Rfree Cruickshank DPI: 0.137
RfactorNum. reflection% reflectionSelection details
Rfree0.236 1188 5.02 %RANDOM
Rwork0.211 ---
obs0.212 23673 99.1 %-
Displacement parametersBiso mean: 44.3 Å2
Baniso -1Baniso -2Baniso -3
1-0.3607 Å20 Å20 Å2
2---4.7129 Å20 Å2
3---4.3522 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.894→38.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2082 0 79 86 2247
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014322HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.037783HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d965SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes615HARMONIC5
X-RAY DIFFRACTIONt_it4322HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.49
X-RAY DIFFRACTIONt_other_torsion14.39
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion265SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4751SEMIHARMONIC4
LS refinement shellResolution: 1.894→1.97 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2301 133 4.98 %
Rwork0.2228 2540 -
all0.2232 2673 -
obs--99.08 %

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