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- PDB-6x3o: Co-structure of BTK kinase domain with L-005191930 inhibitor -

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Basic information

Entry
Database: PDB / ID: 6x3o
TitleCo-structure of BTK kinase domain with L-005191930 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) / 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 / 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-ULY / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 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
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,3656
Polymers63,1972
Non-polymers2,1684
Water6,197344
1
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6823
Polymers31,5981
Non-polymers1,0842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6823
Polymers31,5981
Non-polymers1,0842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.300, 72.010, 104.390
Angle α, β, γ (deg.)90.000, 91.400, 90.000
Int Tables number4
Space group name H-MP1211

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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.: 2
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-ULY / 4-{8-amino-3-[(6R,8aS)-3-oxo-3,5,6,7,8,8a-hexahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide


Mass: 565.546 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H26F3N7O3 / 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.: 2 / Source method: obtained synthetically / Formula: C26H30N8O2S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 344 / 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: 2.28 Å3/Da / Density % sol: 45.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M BIS-TRIS CL pH 7.5, 18%w/vPEG 20,000, 5mM 4-(8-amino-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 5mM (S)- ...Details: 0.1M BIS-TRIS CL pH 7.5, 18%w/vPEG 20,000, 5mM 4-(8-amino-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 5mM (S)-4-(8-amino-3-(1-(4-(dimethylamino)butanoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(thiazol-2-yl)benzamide, 10% v/v deuterated-DMSO

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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: Jun 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→34.79 Å / Num. obs: 44327 / % possible obs: 99.1 % / Redundancy: 2.9 % / Biso Wilson estimate: 27.01 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.048 / Rrim(I) all: 0.084 / Net I/σ(I): 10.8 / Num. measured all: 130298
Reflection shell

Diffraction-ID: 1 / Redundancy: 2.9 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.9-2.120.3236585125800.8660.2210.3913.499.3
4.25-34.790.0351136039820.9960.0250.04325.197.5

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.1.27data scaling
BUSTERrefinement
PDB_EXTRACT3.25data extraction
BUSTER-TNTphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.9→34.79 Å / Cor.coef. Fo:Fc: 0.9478 / Cor.coef. Fo:Fc free: 0.9316 / SU R Cruickshank DPI: 0.279 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.149 / SU Rfree Blow DPI: 0.132 / SU Rfree Cruickshank DPI: 0.134
RfactorNum. reflection% reflectionSelection details
Rfree0.2128 2215 5 %RANDOM
Rwork0.1794 ---
obs0.181 44309 98.95 %-
Displacement parametersBiso max: 121.84 Å2 / Biso mean: 33.5 Å2 / Biso min: 9.35 Å2
Baniso -1Baniso -2Baniso -3
1-2.0895 Å20 Å21.2812 Å2
2--0.1546 Å20 Å2
3----2.2441 Å2
Refine analyzeLuzzati coordinate error obs: 0.199 Å
Refinement stepCycle: final / Resolution: 1.9→34.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4353 0 500 0 4853
Biso mean--39.42 --
Num. residues----532
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2027SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes112HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1284HARMONIC5
X-RAY DIFFRACTIONt_it9042HARMONIC20
X-RAY DIFFRACTIONt_chiral_improper_torsion558SEMIHARMONIC5
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9805SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9042HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg16266HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.43
X-RAY DIFFRACTIONt_other_torsion15.11
LS refinement shellResolution: 1.9→1.95 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2445 156 4.89 %
Rwork0.2064 3033 -
all0.2082 3189 -
obs--98.95 %

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