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- PDB-8ejb: Bruton's tyrosine kinase in complex with 3-{[4-(1-acetylpiperidin... -

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Basic information

Entry
Database: PDB / ID: 8ejb
TitleBruton's tyrosine kinase in complex with 3-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / protein degradation / leukemia
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
PALLADIUM ION / Chem-WKC / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.58 Å
AuthorsGajewski, S. / Clifton, M.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Blood / Year: 2023
Title: NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts.
Authors: Zhang, D. / Harris, H.M. / Chen, J. / Judy, J. / James, G. / Kelly, A. / McIntosh, J. / Tenn-McClellan, A. / Ambing, E. / Tan, Y.S. / Lu, H. / Gajewski, S. / Clifton, M.C. / Yung, S. / ...Authors: Zhang, D. / Harris, H.M. / Chen, J. / Judy, J. / James, G. / Kelly, A. / McIntosh, J. / Tenn-McClellan, A. / Ambing, E. / Tan, Y.S. / Lu, H. / Gajewski, S. / Clifton, M.C. / Yung, S. / Robbins, D.W. / Pirooznia, M. / Skanland, S.S. / Gaglione, E. / Mhibik, M. / Underbayev, C. / Ahn, I.E. / Sun, C. / Herman, S.E.M. / Noviski, M. / Wiestner, A.
History
DepositionSep 16, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 12, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)32,2566
Polymers31,5111
Non-polymers7455
Water5,368298
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.210, 76.240, 105.870
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Tyrosine-protein kinase BTK / Agammaglobulinemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK / Bruton tyrosine kinase


Mass: 31511.209 Da / Num. of mol.: 1
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

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Non-polymers , 5 types, 303 molecules

#2: Chemical ChemComp-WKC / 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-[4-(piperidin-4-yl)anilino]pyrazine-2-carboxamide


Mass: 478.590 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-PD / PALLADIUM ION


Mass: 106.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Pd
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 298 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.42 Å3/Da / Density % sol: 49.2 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 12.5% w/v PEG 1000, 12.5% w/v PEG 3350, 12.5% v/v MPD 0.02 M sodium formate, 0.02 M ammonium acetate, 0.02 M trisodium citrate, 0.02 M sodium potassium l-tartrate, 0.02 M sodium oxamate 0.1 ...Details: 12.5% w/v PEG 1000, 12.5% w/v PEG 3350, 12.5% v/v MPD 0.02 M sodium formate, 0.02 M ammonium acetate, 0.02 M trisodium citrate, 0.02 M sodium potassium l-tartrate, 0.02 M sodium oxamate 0.1 M MES/imidazole pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.58→76.24 Å / Num. obs: 42996 / % possible obs: 99.4 % / Redundancy: 7.9 % / Biso Wilson estimate: 17.12 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.136 / Rpim(I) all: 0.051 / Rrim(I) all: 0.146 / Net I/σ(I): 10.2
Reflection shellResolution: 1.58→1.62 Å / Redundancy: 7.9 % / Rmerge(I) obs: 1.677 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 3068 / CC1/2: 0.549 / Rpim(I) all: 0.864 / Rrim(I) all: 1.793 / % possible all: 98.6

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3GEN

3gen


Resolution: 1.58→52.94 Å / SU ML: 0.1798 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.2529
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.191 2084 4.85 %
Rwork0.1681 40845 -
obs0.1692 42929 99.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.72 Å2
Refinement stepCycle: LAST / Resolution: 1.58→52.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2185 0 45 298 2528
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00892334
X-RAY DIFFRACTIONf_angle_d0.95363162
X-RAY DIFFRACTIONf_chiral_restr0.057332
X-RAY DIFFRACTIONf_plane_restr0.0094399
X-RAY DIFFRACTIONf_dihedral_angle_d7.5803328
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.58-1.620.30471380.2732637X-RAY DIFFRACTION98.16
1.62-1.660.30671360.25072669X-RAY DIFFRACTION97.94
1.66-1.70.25331450.23652637X-RAY DIFFRACTION99.22
1.7-1.750.25191300.21382644X-RAY DIFFRACTION98.09
1.75-1.810.21981290.21262727X-RAY DIFFRACTION99.44
1.81-1.870.23861450.20692655X-RAY DIFFRACTION99.08
1.87-1.950.21711410.18662695X-RAY DIFFRACTION98.85
1.95-2.040.19171300.16542720X-RAY DIFFRACTION99.06
2.04-2.140.17521400.15472699X-RAY DIFFRACTION99.54
2.14-2.280.17181460.15172709X-RAY DIFFRACTION99.72
2.28-2.450.16971360.16422761X-RAY DIFFRACTION99.79
2.45-2.70.20741260.16892770X-RAY DIFFRACTION99.97
2.7-3.090.20271330.16882773X-RAY DIFFRACTION99.93
3.09-3.90.17641550.14872805X-RAY DIFFRACTION99.9
3.9-52.940.15321540.14162944X-RAY DIFFRACTION99.81
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)
13.534111995810.658400093733-2.530667440280.542694651521-1.027942334697.21842107424-0.124219086478-0.3384430888160.136254414274-0.02522548704310.0941190328790.002337756515660.0155480207567-0.105474297646-0.01705045846810.2128977042760.03307918346430.02037128685160.211536752048-0.03662497547020.2420205870023.639863000440.382094521989-0.864147065353
23.494682354820.3691359281210.6318439336670.940749143464-0.4141344446666.84569131272-0.05510391989650.1763402184490.2376280958660.02709854378390.0195671451369-0.00150104945337-0.1016670449410.447554226501-0.01483306355820.1653790317830.0199330711361-0.004978063727470.107871878672-0.009767213871150.180079541936.90048151079-0.853359058842-11.6212776545
30.921251389513-0.615334216990.301570654961.2205770222-0.3794979008280.442120500078-0.0220481172681-0.106833617112-0.007747000939960.09615997709050.07561976848460.0561821417633-0.0226340459567-0.0358893067937-0.06124682908890.1558650287980.009511419877180.01599453310120.171293987937-0.00295965530410.138190609114-1.24247663486-5.63648218856-6.76360685197
41.20190792389-0.190524662971-0.5118023888440.2560186464810.3936109841720.987704544142-0.01468403462240.0111923923952-0.0375266730922-0.02210780946420.0424326109874-0.05337040043690.00739864525993-0.00552315396921-0.02818165692440.1396755455970.00482692410024-0.01453707988460.1439375601630.007313806354950.14655157350413.0226788449-17.5244266957-13.9816188442
52.47815878715-0.7944618416710.5542988416220.642378536151-0.3073459507960.539699027703-0.0161994806225-0.0774316568038-0.05576346808210.001264404146830.01507342679240.048740555059-0.0478640175045-0.03247024619280.01161242157410.136823862941-0.00150409152344-0.002288047208450.151483518275-0.009210084264570.1598928868191.68133156056-14.1827302844-15.9943423813
61.6787284772-0.1307175326460.3876773285020.7957980275780.01759017923741.32857517099-0.03213075796230.0997889991127-0.0290708832048-0.03387175434620.0138465631802-0.0111201511854-0.02842728261460.01695754255280.0222140125010.112733551792-0.00585162688917-0.001071755328160.110570954323-0.01101177884790.1319792834444.06672629996-25.6304933985-28.1927865834
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 389 through 407 )389 - 4071 - 19
22chain 'A' and (resid 408 through 421 )408 - 42120 - 33
33chain 'A' and (resid 422 through 470 )422 - 47034 - 82
44chain 'A' and (resid 471 through 515 )471 - 51583 - 127
55chain 'A' and (resid 516 through 552 )516 - 552128 - 164
66chain 'A' and (resid 553 through 643 )553 - 643165 - 255

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