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- PDB-6x3n: Co-structure of BTK kinase domain with L-005085737 inhibitor -

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Basic information

Entry
Database: PDB / ID: 6x3n
TitleCo-structure of BTK kinase domain with L-005085737 inhibitor
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / Bruton tyrosine kinase inhibitor
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) / positive regulation of immunoglobulin production / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / 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 B cell proliferation / positive regulation of phagocytosis / 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 / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / 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 / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-5WE / Chem-ULV / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.95 Å
AuthorsFischmann, T.O.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.
Authors: Liu, J. / Guiadeen, D. / Krikorian, A. / Gao, X. / Wang, J. / Babu Boga, S. / Alhassan, A.B. / Yu, W. / Selyutin, O. / Yu, Y. / Anand, R. / Xu, J. / Kelly, J. / Duffy, J.L. / Liu, S. / Yang, ...Authors: Liu, J. / Guiadeen, D. / Krikorian, A. / Gao, X. / Wang, J. / Babu Boga, S. / Alhassan, A.B. / Yu, W. / Selyutin, O. / Yu, Y. / Anand, R. / Xu, J. / Kelly, J. / Duffy, J.L. / Liu, S. / Yang, C. / Wu, H. / Cai, J. / Bennett, C. / Maloney, K.M. / Tyagarajan, S. / Gao, Y.D. / Fischmann, T.O. / Presland, J. / Mansueto, M. / Xu, Z. / Leccese, E. / Zhang-Hoover, J. / Knemeyer, I. / Garlisi, C.G. / Stivers, P. / Brandish, P.E. / Hicks, A. / Kim, R. / Kozlowski, J.A.
History
DepositionMay 21, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 12, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)32,6543
Polymers31,5981
Non-polymers1,0562
Water1,33374
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.410, 104.830, 38.100
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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
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-ULV / 4-{8-amino-3-[(6R,8aS)-3-oxohexahydro-3H-[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide


Mass: 537.493 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22F3N7O3 / Feature type: SUBJECT OF INVESTIGATION
#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


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.29 Å3/Da / Density % sol: 46.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M Bis-TRIS pH 6.5, 0.1M NaCl, 15% w/v PEG 20K 5mM TCEP Cl, 4mM (S)-4-(8-amino-3-(1-(4-(dimethylamino)butanoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(thiazol-2-yl)benzamide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 13, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 21501 / % possible obs: 98.3 % / Redundancy: 6 % / Biso Wilson estimate: 37.13 Å2 / Rmerge(I) obs: 0.086 / Χ2: 0.832 / Net I/σ(I): 5.4 / Num. measured all: 128974
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.95-1.986.30.43910420.485196.5
1.98-2.026.20.3910300.514196.2
2.02-2.066.10.34610670.559199.6
2.06-2.16.10.30710280.578196.3
2.1-2.1560.26210560.593197.6
2.15-2.25.70.22810510.647199.8
2.2-2.256.20.21310380.674195.7
2.25-2.315.90.18810690.671199.9
2.31-2.386.40.1710520.698196.6
2.38-2.466.30.15410570.75199.7
2.46-2.546.20.1410840.794197.3
2.54-2.656.30.12610690.837199.8
2.65-2.775.70.11210690.843198
2.77-2.9160.10710810.908199.4
2.91-3.16.10.09210760.924198.9
3.1-3.336.20.08710771.062199
3.33-3.6760.07811081.23199.1
3.67-4.25.50.07211161.304199.3
4.2-5.295.70.06711301.265199.1
5.29-505.20.06112011.349198.1

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Processing

Software
NameVersionClassification
DENZO2.3.1data reduction
SCALEPACKdata scaling
BUSTER2.11.2refinement
PDB_EXTRACT3.25data extraction
BUSTER-TNTphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.95→31.47 Å / Cor.coef. Fo:Fc: 0.9392 / Cor.coef. Fo:Fc free: 0.9268 / SU R Cruickshank DPI: 0.304 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.177 / SU Rfree Blow DPI: 0.152 / SU Rfree Cruickshank DPI: 0.152
RfactorNum. reflection% reflectionSelection details
Rfree0.2417 1082 5.04 %RANDOM
Rwork0.2136 ---
obs0.215 21456 98.09 %-
Displacement parametersBiso max: 149.79 Å2 / Biso mean: 46.72 Å2 / Biso min: 21.41 Å2
Baniso -1Baniso -2Baniso -3
1--3.1261 Å20 Å20 Å2
2---0.7443 Å20 Å2
3---3.8704 Å2
Refine analyzeLuzzati coordinate error obs: 0.227 Å
Refinement stepCycle: final / Resolution: 1.95→31.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2079 0 150 0 2229
Biso mean--47.73 --
Num. residues----254
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d959SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes608HARMONIC5
X-RAY DIFFRACTIONt_it4297HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion264SEMIHARMONIC5
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_contact4562SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4297HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7736HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion3.58
X-RAY DIFFRACTIONt_other_torsion14.55
LS refinement shellResolution: 1.95→2.04 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.243 140 5.16 %
Rwork0.1979 2575 -
all0.2003 2715 -
obs--98.09 %

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