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- PDB-5p9g: Structure of BTK with RN486 -

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Basic information

Entry
Database: PDB / ID: 5p9g
TitleStructure of BTK with RN486
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / kinase / kinase-ligand 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 / histamine secretion by mast cell / positive regulation of synoviocyte proliferation ...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 / histamine secretion by mast cell / positive regulation of synoviocyte proliferation / 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 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 / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / mesoderm development / positive regulation of immunoglobulin production / 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 / calcium-mediated signaling / 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 / positive regulation of interleukin-6 production / peptidyl-tyrosine phosphorylation / G alpha (12/13) signalling events / positive regulation of tumor necrosis factor production / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / T cell receptor signaling pathway / cytoplasmic vesicle / G alpha (q) signalling events / protein tyrosine kinase activity / Potential therapeutics for SARS / response to lipopolysaccharide / adaptive immune response / 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 / Src homology 3 domains / SH2 domain / 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-7G6 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 Å
AuthorsGardberg, A.S.
CitationJournal: Mol. Pharmacol. / Year: 2017
Title: Ability of Bruton's Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling.
Authors: Bender, A.T. / Gardberg, A. / Pereira, A. / Johnson, T. / Wu, Y. / Grenningloh, R. / Head, J. / Morandi, F. / Haselmayer, P. / Liu-Bujalski, L.
History
DepositionSep 20, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 24, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type
Revision 1.2Nov 17, 2021Group: Data collection / Database references / Structure summary
Category: database_2 / diffrn_radiation_wavelength / pdbx_deposit_group
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_deposit_group.group_description

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9332
Polymers32,3261
Non-polymers6071
Water2,882160
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.090, 104.420, 38.380
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: 32326.068 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: Trichoplusia ni (cabbage looper) / Strain (production host): Hi5
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-7G6 / 6-cyclopropyl-8-fluoranyl-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]-6-oxidanylidene-pyridin-3-yl]phenyl]isoquinolin-1-one


Mass: 606.689 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H35FN6O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 160 / 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: 44.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7 / Details: PEG 3350, sodium actate, BisTrisPropane

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 4, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.75→42.285 Å / Num. obs: 29749 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 31.714 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.054 / Rrim(I) all: 0.059 / Χ2: 1.089 / Net I/σ(I): 20.15 / Num. measured all: 189866
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.75-1.860.5512.8528798473846610.8590.60298.4
1.86-1.990.3135.1529471445044430.960.3499.8
1.99-2.150.1828.9727727419841970.9850.197100
2.15-2.350.11613.5924453383238320.9930.127100
2.35-2.630.07820.8523325349734940.9970.08599.9
2.63-3.030.05429.3619575313231260.9980.05999.8
3.03-3.710.03545.5317106266626540.9990.03899.5
3.71-5.220.02756.0512318209620890.9990.0399.7
5.22-42.2850.02356.6670931263125310.02599.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0005refinement
XSCALEdata scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→36.04 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.941 / WRfactor Rfree: 0.2068 / WRfactor Rwork: 0.1725 / FOM work R set: 0.8951 / SU B: 4.199 / SU ML: 0.063 / SU R Cruickshank DPI: 0.1107 / SU Rfree: 0.1091 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.111 / ESU R Free: 0.109 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2135 1488 5 %RANDOM
Rwork0.1775 ---
obs0.1792 28260 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 68.53 Å2 / Biso mean: 26.58 Å2 / Biso min: 12.35 Å2
Baniso -1Baniso -2Baniso -3
1-0.92 Å20 Å20 Å2
2---0.57 Å20 Å2
3----0.36 Å2
Refinement stepCycle: final / Resolution: 1.75→36.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2108 0 45 160 2313
Biso mean--25.72 27.28 -
Num. residues----265
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0222219
X-RAY DIFFRACTIONr_bond_other_d0.0020.021929
X-RAY DIFFRACTIONr_angle_refined_deg1.6921.9763012
X-RAY DIFFRACTIONr_angle_other_deg0.81434463
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1025266
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.37923.63699
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.73315368
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.5741512
X-RAY DIFFRACTIONr_chiral_restr0.1050.2319
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022477
X-RAY DIFFRACTIONr_gen_planes_other00.02465
X-RAY DIFFRACTIONr_mcbond_it1.0041.51321
X-RAY DIFFRACTIONr_mcbond_other0.3281.5539
X-RAY DIFFRACTIONr_mcangle_it1.84722117
X-RAY DIFFRACTIONr_scbond_it2.9643898
X-RAY DIFFRACTIONr_scangle_it4.6754.5891
LS refinement shellResolution: 1.753→1.799 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.248 104 -
Rwork0.233 1973 -
all-2077 -
obs--100 %
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)
11.98561.2945-0.05775.4658-0.81783.4-0.1737-0.1443-0.2122-0.20220.0670.08810.28020.07150.10670.1410.0630.05420.04420.02160.116618.805-3.7595.583
20.82660.005-0.28270.982-0.24131.4913-0.0454-0.0247-0.1283-0.00590.02780.05490.20860.03010.01760.03880.011-0.00430.0108-0.00090.032814.75211.2875.764
31.06781.7661-1.902710.8313-3.55183.51640.0312-0.13950.00630.489-0.1321-0.306-0.09440.15920.10090.03710.0144-0.04660.1374-0.05280.100129.23819.59517.229
41.97230.3693-0.09350.8383-0.12741.93730.09050.00160.08610.0272-0.00840.0466-0.2190.0457-0.08210.0428-0.00190.00760.0075-0.00630.011416.3130.0254.862
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-10 - 431
2X-RAY DIFFRACTION2A432 - 548
3X-RAY DIFFRACTION3A549 - 557
4X-RAY DIFFRACTION4A558 - 659

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