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- PDB-7kxn: BTK1 SOAKED WITH COMPOUND 26 -

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Basic information

Entry
Database: PDB / ID: 7kxn
TitleBTK1 SOAKED WITH COMPOUND 26
ComponentsIsoform BTK-C of Tyrosine-protein kinase BTK
KeywordsTRANSFERASE
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 / adaptive immune response / response to lipopolysaccharide / 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 / 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-X9P / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.34 Å
AuthorsViacava Follis, A.
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors.
Authors: Qiu, H. / Ali, Z. / Bender, A. / Caldwell, R. / Chen, Y.Y. / Fang, Z. / Gardberg, A. / Glaser, N. / Goettsche, A. / Goutopoulos, A. / Grenningloh, R. / Hanschke, B. / Head, J. / Johnson, T. ...Authors: Qiu, H. / Ali, Z. / Bender, A. / Caldwell, R. / Chen, Y.Y. / Fang, Z. / Gardberg, A. / Glaser, N. / Goettsche, A. / Goutopoulos, A. / Grenningloh, R. / Hanschke, B. / Head, J. / Johnson, T. / Jones, C. / Jones, R. / Kulkarni, S. / Maurer, C. / Morandi, F. / Neagu, C. / Poetzsch, S. / Potnick, J. / Schmidt, R. / Roe, K. / Viacava Follis, A. / Wing, C. / Zhu, X. / Sherer, B.
History
DepositionDec 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform BTK-C of Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9034
Polymers31,2081
Non-polymers6953
Water4,864270
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.497, 103.340, 38.619
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 Isoform BTK-C of Tyrosine-protein kinase BTK / Agammaglobulinemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK / Bruton tyrosine kinase


Mass: 31207.855 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: Escherichia coli (E. coli)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-X9P / 3-tert-butyl-N-[(1S)-6-{2-[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide


Mass: 538.643 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H34N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 270 / 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: 2.32 Å3/Da / Density % sol: 46.93 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG 3350 0.1 M Bis Tris Propane pH 7.5 0.2 M Sodium acetate trihydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X1A / Wavelength: 0.99996 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99996 Å / Relative weight: 1
ReflectionResolution: 1.34→59.35 Å / Num. obs: 65405 / % possible obs: 98.9 % / Redundancy: 4.54 % / Rmerge(I) obs: 0.058 / Net I/σ(I): 13.81
Reflection shellResolution: 1.34→1.42 Å / Redundancy: 4.48 % / Rmerge(I) obs: 0.852 / Mean I/σ(I) obs: 1.84 / Num. unique obs: 65405 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1k2p

1k2p


Resolution: 1.34→59.35 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.959 / SU B: 2.304 / SU ML: 0.042 / Cross valid method: FREE R-VALUE / σ(F): 0 / ESU R: 0.06 / ESU R Free: 0.057 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1965 6022 9.2 %RANDOM
Rwork0.1643 ---
obs0.1673 59357 99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 56.16 Å2 / Biso mean: 17.346 Å2 / Biso min: 8.43 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å20 Å2
2--0.62 Å2-0 Å2
3----0.8 Å2
Refinement stepCycle: final / Resolution: 1.34→59.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2182 0 48 270 2500
Biso mean--19.68 25.67 -
Num. residues----266
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.022363
X-RAY DIFFRACTIONr_bond_other_d0.0010.022190
X-RAY DIFFRACTIONr_angle_refined_deg1.111.983203
X-RAY DIFFRACTIONr_angle_other_deg0.6323.0055105
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0785287
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.3324.196112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.24115446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5461513
X-RAY DIFFRACTIONr_chiral_restr0.0760.2336
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022586
X-RAY DIFFRACTIONr_gen_planes_other00.02495
X-RAY DIFFRACTIONr_rigid_bond_restr8.31832342
X-RAY DIFFRACTIONr_sphericity_free14.442541
X-RAY DIFFRACTIONr_sphericity_bonded6.68552473
LS refinement shellResolution: 1.34→1.375 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 475 -
Rwork0.283 4319 -
all-4794 -
obs--99.56 %
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)
10.3204-0.05720.45151.3660.4341.266-0.0197-0.1039-0.0850.13880.03870.11840.2136-0.0798-0.0190.13480.01940.01970.0560.01980.134716.45551.4899.2521
22.5897-0.4482-0.72929.1227-2.70245.19860.1982-0.23050.1592-0.0291-0.2175-0.392-0.14030.28040.01930.08790.0003-0.01230.128-0.00120.102128.431618.391916.7807
31.25020.0415-0.16881.1305-0.00711.34270.0003-0.02710.04330.00330.02480.0403-0.0518-0.0107-0.02510.02230.0056-0.00380.00260.00080.069914.772425.82992.9608
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A389 - 481
2X-RAY DIFFRACTION1A531 - 546
3X-RAY DIFFRACTION2A547 - 560
4X-RAY DIFFRACTION3A482 - 530
5X-RAY DIFFRACTION3A561 - 659

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