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- PDB-5u9d: Discovery of a potent BTK inhibitor with a novel binding mode usi... -

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Basic information

Entry
Database: PDB / ID: 5u9d
TitleDiscovery of a potent BTK inhibitor with a novel binding mode using parallel selections with a DNA-encoded chemical library
ComponentsTyrosine-protein kinase BTK
KeywordsANTITUMOR PROTEIN / Brutons tyrosine kinase / BTK / PROTEIN KINASE / DNA encoded library / PROTEROS BIOSTRUCTURES GMBH
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 / 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 / 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-83P / DI(HYDROXYETHYL)ETHER / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.33 Å
AuthorsCuozzo, J.W. / Centrella, P.A. / Gikunju, D. / Habeshian, S. / Hupp, C.D. / Keefe, A.D. / Sigel, E. / Soutter, H.H. / Thomson, H.A. / Zhang, Y. / Clark, M.A.
CitationJournal: Chembiochem / Year: 2017
Title: Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA-Encoded Chemical Library.
Authors: Cuozzo, J.W. / Centrella, P.A. / Gikunju, D. / Habeshian, S. / Hupp, C.D. / Keefe, A.D. / Sigel, E.A. / Soutter, H.H. / Thomson, H.A. / Zhang, Y. / Clark, M.A.
History
DepositionDec 16, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2017Group: Database references
Revision 1.2May 10, 2017Group: Database references
Revision 1.3Mar 6, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)32,4777
Polymers31,5981
Non-polymers8796
Water6,089338
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.553, 103.483, 37.839
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 423-693
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: unidentified baculovirus
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-83P / (R)-N-methyl-2-(3-((quinoxalin-6-ylamino)methyl)furan-2-carbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide / (3R)-N-methyl-2-(3-{[(quinoxalin-6-yl)amino]methyl}furan-2-carbonyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxamide


Mass: 480.518 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H24N6O3
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 338 / 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: 2.3 Å3/Da / Density % sol: 46.5 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: Polyethylene glycols (PEG3350 / PEG5000MME), (NH4)2SO4 and MES buffer at pH6.0-6.7
PH range: 6.0-6.7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Aug 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.33→58.85 Å / Num. obs: 65295 / % possible obs: 99.7 % / Redundancy: 7.9 % / Net I/av σ(I): 5.03 / Net I/σ(I): 23.8
Reflection shellResolution: 1.33→1.538 Å / Redundancy: 7.7 % / Rmerge(I) obs: 0.434 / Mean I/σ(I) obs: 5.03 / % possible all: 99.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XSCALEdata scaling
MOLREPphasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 1.33→58.85 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.966 / SU B: 1.957 / SU ML: 0.035 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.059 / ESU R Free: 0.054
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1783 6526 10 %RANDOM
Rwork0.1484 ---
obs0.1514 58769 99.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 68.85 Å2 / Biso mean: 16.333 Å2 / Biso min: 6 Å2
Baniso -1Baniso -2Baniso -3
1-0.65 Å20 Å2-0 Å2
2---0.39 Å20 Å2
3----0.26 Å2
Refinement stepCycle: final / Resolution: 1.33→58.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2214 0 61 339 2614
Biso mean--20.92 29.07 -
Num. residues----271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192558
X-RAY DIFFRACTIONr_bond_other_d0.0010.022355
X-RAY DIFFRACTIONr_angle_refined_deg1.411.9793480
X-RAY DIFFRACTIONr_angle_other_deg2.94235449
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3335320
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.69623.846117
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.43715450
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9661514
X-RAY DIFFRACTIONr_chiral_restr0.0930.2352
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022977
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02612
X-RAY DIFFRACTIONr_rigid_bond_restr1.53734913
X-RAY DIFFRACTIONr_sphericity_free28.923574
X-RAY DIFFRACTIONr_sphericity_bonded7.32555096
LS refinement shellResolution: 1.33→1.365 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.415 455 -
Rwork0.378 4243 -
all-4698 -
obs--98.31 %

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