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- PDB-6nfh: BTK in complex with inhibitor 8-(2,3-dihydro-1H-inden-5-yl)-2-({4... -

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Basic information

Entry
Database: PDB / ID: 6nfh
TitleBTK in complex with inhibitor 8-(2,3-dihydro-1H-inden-5-yl)-2-({4-[(2S)-3-(dimethylamino)-2-hydroxypropoxy]phenyl}amino)-5,8-dihydropteridine-6,7-dione
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Bruton Tyrosine kinase / BTK / Kinase / BTK inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of B cell cytokine production / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / proteoglycan catabolic process / 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 / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / proteoglycan catabolic process / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / positive regulation of cGAS/STING signaling pathway / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / positive regulation of immunoglobulin production / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / positive regulation of NLRP3 inflammasome complex assembly / Fc-epsilon receptor signaling pathway / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / B cell activation / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / cell maturation / positive regulation of B cell proliferation / FCERI mediated Ca+2 mobilization / positive regulation of phagocytosis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / peptidyl-tyrosine phosphorylation / cellular response to reactive oxygen species / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / apoptotic signaling pathway / calcium-mediated signaling / positive regulation of NF-kappaB transcription factor activity / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / G beta:gamma signalling through BTK / positive regulation of tumor necrosis factor production / DAP12 signaling / G alpha (12/13) signalling events / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / protein tyrosine kinase activity / response to lipopolysaccharide / G alpha (q) signalling events / adaptive immune response / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / intracellular signal transduction / membrane raft / innate immune response / perinuclear region of cytoplasm / zinc ion binding / ATP binding / identical protein binding / nucleus / 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 ...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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-KLM / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsMirzadegan, T. / Damm-Ganamet, K.L.
CitationJournal: J.Chem.Inf.Model. / Year: 2019
Title: Accelerating Lead Identification by High Throughput Virtual Screening: Prospective Case Studies from the Pharmaceutical Industry.
Authors: Damm-Ganamet, K.L. / Arora, N. / Becart, S. / Edwards, J.P. / Lebsack, A.D. / McAllister, H.M. / Nelen, M.I. / Rao, N.L. / Westover, L. / Wiener, J.J.M. / Mirzadegan, T.
History
DepositionDec 20, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 12, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Oct 11, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4598
Polymers31,5981
Non-polymers8617
Water4,972276
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint16 kcal/mol
Surface area13650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.123, 104.367, 38.140
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: 31598.287 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 389-659)
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-KLM / 8-(2,3-dihydro-1H-inden-5-yl)-2-({4-[(2S)-3-(dimethylamino)-2-hydroxypropoxy]phenyl}amino)-5,8-dihydropteridine-6,7-dione


Mass: 488.538 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28N6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 276 / 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: 2.27 Å3/Da / Density % sol: 45.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 31% w/v PEG5000 MME, 0.1 M MES, pH 6.5, 0.1 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.99987 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: May 14, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.4→59.33 Å / Num. obs: 54763 / % possible obs: 95.2 % / Redundancy: 2.3 % / Rrim(I) all: 0.076 / Rsym value: 0.059 / Net I/σ(I): 10
Reflection shellResolution: 1.4→1.65 Å / Rmerge(I) obs: 0.481 / CC1/2: 0.755

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.5.0109refinement
PDB_EXTRACT3.24data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1K2P

1k2p


Resolution: 1.4→59.33 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.952 / SU B: 2.868 / SU ML: 0.049 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.074 / ESU R Free: 0.07
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2054 5022 9.2 %RANDOM
Rwork0.1558 ---
obs0.1604 49736 95.26 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 78.98 Å2 / Biso mean: 14.678 Å2 / Biso min: 6.14 Å2
Baniso -1Baniso -2Baniso -3
1-1.14 Å20 Å20 Å2
2---0.46 Å20 Å2
3----0.67 Å2
Refinement stepCycle: final / Resolution: 1.4→59.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2214 0 60 276 2550
Biso mean--25.05 29.5 -
Num. residues----271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222480
X-RAY DIFFRACTIONr_bond_other_d0.0020.021730
X-RAY DIFFRACTIONr_angle_refined_deg1.4331.9773363
X-RAY DIFFRACTIONr_angle_other_deg1.41434199
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1715308
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.36123.929112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.29715446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.781514
X-RAY DIFFRACTIONr_chiral_restr0.0910.2345
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022813
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02529
X-RAY DIFFRACTIONr_rigid_bond_restr2.68934210
LS refinement shellResolution: 1.401→1.438 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 375 -
Rwork0.277 3593 -
all-3968 -
obs--94.5 %

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