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- PDB-5fbn: BTK kinase domain with inhibitor 1 -

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Basic information

Entry
Database: PDB / ID: 5fbn
TitleBTK kinase domain with inhibitor 1
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / 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 / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of immunoglobulin production / positive regulation of B cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / mesoderm development / Fc-epsilon receptor signaling pathway / B cell activation / 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 / apoptotic signaling pathway / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / calcium-mediated signaling / Regulation of actin dynamics for phagocytic cup formation / peptidyl-tyrosine phosphorylation / G beta:gamma signalling through BTK / positive regulation of interleukin-6 production / cellular response to reactive oxygen species / 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 / protein tyrosine kinase activity / G alpha (q) signalling events / response to lipopolysaccharide / adaptive immune response / Potential therapeutics for SARS / intracellular signal transduction / protein phosphorylation / membrane raft / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / metal ion binding / 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-5WF / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsRaaijmakers, H.C.A. / Vu-Pham, D.
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: PDBE
Revision 1.0Feb 3, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2016Group: Database references
Revision 1.2Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.3May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Tyrosine-protein kinase BTK
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,56311
Polymers63,1972
Non-polymers3,3679
Water9,314517
1
C: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7324
Polymers31,5981
Non-polymers1,1343
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8317
Polymers31,5981
Non-polymers2,2336
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.262, 71.475, 103.056
Angle α, β, γ (deg.)90.00, 90.68, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11C
21D

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: TRP / Beg label comp-ID: TRP / End auth comp-ID: GLU / End label comp-ID: GLU / Refine code: _ / Auth seq-ID: 395 - 658 / Label seq-ID: 7 - 270

Dom-IDAuth asym-IDLabel asym-ID
1CA
2DB

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Components

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Protein , 1 types, 2 molecules CD

#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.: 2 / Fragment: 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

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Non-polymers , 5 types, 526 molecules

#2: Chemical ChemComp-5WF / 4-[8-azanyl-3-[(3~{R})-1-(3-methyloxetan-3-yl)carbonylpiperidin-3-yl]imidazo[1,5-a]pyrazin-1-yl]-~{N}-[4-(trifluoromethyl)pyridin-2-yl]benzamide


Mass: 579.573 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H28F3N7O3
#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.: 4 / Source method: obtained synthetically / Formula: C26H30N8O2S
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 517 / 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: 2.23 Å3/Da / Density % sol: 44.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 20% v/v PEG 20000 0.1M NaCl 0.1M Na MES pH 6.5 2.5 mM 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 5.0 mM (R)-4-(8- ...Details: 20% v/v PEG 20000 0.1M NaCl 0.1M Na MES pH 6.5 2.5 mM 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 5.0 mM (R)-4-(8-amino-3-(1-(3-methyloxetane-3-carbonyl)piperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide
PH range: 5.0-6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Sep 1, 2010
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.955
11-h,-k,l20.045
ReflectionResolution: 1.8→36 Å / Num. obs: 48820 / % possible obs: 94.7 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.064 / Net I/σ(I): 11.2
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 1.5 / % possible all: 94.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: not deposited inhouse model

Resolution: 1.8→103.05 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.93 / SU B: 5.989 / SU ML: 0.097 / Cross valid method: THROUGHOUT / ESU R: 0.15 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22596 3322 6.8 %RANDOM
Rwork0.17945 ---
obs0.18232 45481 94.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.103 Å2
Baniso -1Baniso -2Baniso -3
1--0.29 Å20 Å2-0.19 Å2
2--0.09 Å20 Å2
3---0.21 Å2
Refinement stepCycle: LAST / Resolution: 1.8→103.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4171 0 234 517 4922
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0194633
X-RAY DIFFRACTIONr_bond_other_d0.0050.024272
X-RAY DIFFRACTIONr_angle_refined_deg1.7482.0146297
X-RAY DIFFRACTIONr_angle_other_deg1.31739836
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2915531
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.68223.942208
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.56615803
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.2561526
X-RAY DIFFRACTIONr_chiral_restr0.1010.2635
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0215175
X-RAY DIFFRACTIONr_gen_planes_other0.0060.021107
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_it0.91.2922096
X-RAY DIFFRACTIONr_mcbond_other0.8971.2912095
X-RAY DIFFRACTIONr_mcangle_it1.541.9252635
X-RAY DIFFRACTIONr_mcangle_other1.5391.9262636
X-RAY DIFFRACTIONr_scbond_it1.1911.5352537
X-RAY DIFFRACTIONr_scbond_other1.1911.5352537
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.9452.2383639
X-RAY DIFFRACTIONr_long_range_B_refined5.38612.4335919
X-RAY DIFFRACTIONr_long_range_B_other5.38612.4365920
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 67594 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.09 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1C
2D
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.398 167 -
Rwork0.333 2405 -
obs--68.26 %
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)
10.76470.0349-0.02760.75550.18381.7366-0.03350.08870.0117-0.08290.0276-0.0710.02370.11360.00590.01160.0020.00780.11840.00110.0073-14.13529.511-9.325
21.1180.0123-0.22370.5986-0.03861.75950.0169-0.1231-0.03520.0657-0.0158-0.0543-0.00970.1416-0.0010.0075-0.0056-0.00620.1027-0.00260.0066-13.3171.151-42.533
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1C395 - 1000
2X-RAY DIFFRACTION2D394 - 1000

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