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- PDB-8e2m: Bruton's tyrosine kinase (BTK) with compound 13 -

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Basic information

Entry
Database: PDB / ID: 8e2m
TitleBruton's tyrosine kinase (BTK) with compound 13
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / PROTEIN KINASE / INHIBITOR / COVALENT / 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 / 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 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 / 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
TRIETHYLENE GLYCOL / Chem-UB6 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.904 Å
AuthorsAlexander, R. / Milligan, C.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
Authors: Tichenor, M.S. / Wiener, J.J.M. / Rao, N.L. / Bacani, G.M. / Wei, J. / Pooley Deckhut, C. / Barbay, J.K. / Kreutter, K.D. / Chang, L. / Clancy, K.W. / Murrey, H.E. / Wang, W. / Ahn, K. / ...Authors: Tichenor, M.S. / Wiener, J.J.M. / Rao, N.L. / Bacani, G.M. / Wei, J. / Pooley Deckhut, C. / Barbay, J.K. / Kreutter, K.D. / Chang, L. / Clancy, K.W. / Murrey, H.E. / Wang, W. / Ahn, K. / Huber, M. / Rex, E. / Coe, K.J. / Wu, J. / Rui, H. / Sepassi, K. / Gaudiano, M. / Bekkers, M. / Cornelissen, I. / Packman, K. / Seierstad, M. / Xiouras, C. / Bembenek, S.D. / Alexander, R. / Milligan, C. / Balasubramanian, S. / Lebsack, A.D. / Venable, J.D. / Philippar, U. / Edwards, J.P. / Hirst, G.
History
DepositionAug 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)32,2693
Polymers31,5981
Non-polymers6712
Water4,702261
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.155, 72.394, 103.946
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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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 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-UB6 / (5P)-5-[4-methyl-6-(2-methylpropyl)pyridin-3-yl]-4-oxo-N-[(1R,2S)-2-propanamidocyclopentyl]-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide


Mass: 520.646 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32N6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 261 / 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: 2.27 Å3/Da / Density % sol: 45.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 25-33% PEG-5000 MME, 100 mM MES pH 6.35-6.75, 200 mM Ammonium Sulfate

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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: Oct 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 23105 / % possible obs: 99.4 % / Redundancy: 4.3 % / Biso Wilson estimate: 14.66 Å2 / Rmerge(I) obs: 0.124 / Rpim(I) all: 0.065 / Rrim(I) all: 0.141 / Χ2: 1.076 / Net I/σ(I): 15.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.934.10.54311030.8350.290.6180.85198.4
1.93-1.9740.47911020.870.2540.5440.86798.3
1.97-2.014.30.4211560.9070.2140.4740.94399
2.01-2.054.50.4111040.9110.2040.460.90299.5
2.05-2.094.40.3711490.9190.1850.4150.91499.4
2.09-2.144.40.31911380.9450.160.3580.93999.6
2.14-2.194.40.28911390.960.1470.3250.97399.7
2.19-2.254.30.24411520.9610.1250.2750.9899.1
2.25-2.324.30.22111220.9690.1140.251.00499.5
2.32-2.3940.19411640.9670.1020.2211.0499.6
2.39-2.484.40.17211380.9790.0890.1950.99199.9
2.48-2.584.20.14511620.9840.0770.1651.01699.7
2.58-2.74.60.13811450.9850.070.1560.98599.4
2.7-2.844.50.12411440.9880.0640.141.00299.5
2.84-3.024.40.10711730.990.0560.1221.144100
3.02-3.254.30.0911520.990.0480.1031.27998.8
3.25-3.584.10.07411720.9920.040.0841.33899.2
3.58-4.094.20.0611850.9940.0330.0691.446100
4.09-5.164.30.05912150.9950.0320.0671.497100
5.16-503.90.05612900.9960.0310.0651.3899.1

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.47 Å38.16 Å
Translation6.47 Å38.16 Å

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.6.0phasing
PHENIX1.10_2155refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Internal Previously Solved BTK Structure

Resolution: 1.904→38.155 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 18.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1991 2000 8.67 %
Rwork0.1539 21063 -
obs0.1579 23063 99.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 78.01 Å2 / Biso mean: 18.945 Å2 / Biso min: 4.84 Å2
Refinement stepCycle: final / Resolution: 1.904→38.155 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2208 0 90 261 2559
Biso mean--24.53 27.72 -
Num. residues----270
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092410
X-RAY DIFFRACTIONf_angle_d0.873264
X-RAY DIFFRACTIONf_chiral_restr0.055336
X-RAY DIFFRACTIONf_plane_restr0.005415
X-RAY DIFFRACTIONf_dihedral_angle_d15.4931433
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.9044-1.9520.27471300.1871137793
1.952-2.00480.24051420.1711149399
2.0048-2.06380.24661390.1638146099
2.0638-2.13040.21671420.16241492100
2.1304-2.20650.21131410.1561488100
2.2065-2.29480.21791400.1594147499
2.2948-2.39930.19641440.15821524100
2.3993-2.52570.21081420.1541492100
2.5257-2.68390.2331430.15921505100
2.6839-2.89110.21061440.16631509100
2.8911-3.18190.19091440.159152399
3.1819-3.6420.19381450.1452151699
3.642-4.58730.14091480.12541564100
4.5873-38.1550.18151560.1563164699
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)
13.1878-1.3925-0.93953.62980.28712.7681-0.0804-0.09550.14390.07610.052-0.2102-0.1130.3929-0.01550.1361-0.0313-0.01920.17140.01530.0852-11.5405-17.3235-4.5913
22.3125-0.03510.00230.5632-0.10581.9999-0.0610.26510.0903-0.02920.0182-0.0932-0.00740.30560.03010.1112-0.0114-0.00190.14440.00980.0969-8.521-20.34921.6534
34.3465-0.9279-0.40471.11940.19251.4385-0.00810.0697-0.047-0.01660.0117-0.01730.02510.0101-0.0080.0905-0.0144-0.00240.04910.00020.0614-19.2704-22.93816.4499
43.6861-0.9614-4.95780.78541.01946.80920.41220.08080.3737-0.2011-0.0687-0.1474-0.7241-0.0562-0.31330.1655-0.00420.01410.14160.00640.1497-3.6761-10.501719.0289
52.27290.1052-0.18160.98590.09060.9307-0.0233-0.13950.04980.08740.0258-0.03610.00010.0605-0.00360.09770-0.01410.05040.00230.0719-12.9658-17.884231.2193
65.75275.0046-1.18764.6135-1.84422.84440.2016-0.20760.16080.1667-0.13240.19140.0047-0.1511-0.06810.1726-0.00150.00470.056-0.02420.1049-20.7017-34.374127.0776
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 389 through 421 )A389 - 421
2X-RAY DIFFRACTION2chain 'A' and (resid 422 through 481 )A422 - 481
3X-RAY DIFFRACTION3chain 'A' and (resid 482 through 541 )A482 - 541
4X-RAY DIFFRACTION4chain 'A' and (resid 542 through 565 )A542 - 565
5X-RAY DIFFRACTION5chain 'A' and (resid 566 through 643 )A566 - 643
6X-RAY DIFFRACTION6chain 'A' and (resid 644 through 658 )A644 - 658

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