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- PDB-5j87: Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phen... -

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Basic information

Entry
Database: PDB / ID: 5j87
TitleDiscovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a Highly Selective Irreversible BTK Kinase Inhibitor
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / BTK / 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 / G beta:gamma signalling through BTK / Regulation of actin dynamics for phagocytic cup formation / 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 / 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 / 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 / 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-N42 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.59 Å
AuthorsYun, C.H. / Zhang, S.
CitationJournal: Eur J Med Chem / Year: 2017
Title: Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective ...Title: Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor.
Authors: Liang, Q. / Chen, Y. / Yu, K. / Chen, C. / Zhang, S. / Wang, A. / Wang, W. / Wu, H. / Liu, X. / Wang, B. / Wang, L. / Hu, Z. / Wang, W. / Ren, T. / Zhang, S. / Liu, Q. / Yun, C.H. / Liu, J.
History
DepositionApr 7, 2016Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Apr 19, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
B: Tyrosine-protein kinase BTK
C: Tyrosine-protein kinase BTK
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,0618
Polymers127,4704
Non-polymers2,5914
Water15,565864
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.761, 93.550, 145.889
Angle α, β, γ (deg.)90.00, 89.94, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 31867.584 Da / Num. of mol.: 4 / Fragment: UNP RESIDUES 385-658
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-N42 / N-[3-(5-{[3-(acryloylamino)-4-(morpholine-4-carbonyl)phenyl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4-tert-butylbenzamide


Mass: 647.763 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C38H41N5O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 864 / 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: 2.29 Å3/Da / Density % sol: 46.36 %
Crystal growTemperature: 298 K / Method: evaporation / pH: 6.5
Details: 0.2M magnesium chloride ,0.1M sodium cacodylate pH6.5, 31% PEG 2000 , 0.1M sodium iodide

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Data collection

DiffractionMean temperature: 193 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.978 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Oct 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.59→48.63 Å / Num. obs: 136878 / % possible obs: 91 % / Redundancy: 6 % / Net I/σ(I): 15.8

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-3000data scaling
RefinementResolution: 1.59→48.63 Å / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 25.07 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.2477 7168 5.24 %
Rwork0.2165 --
obs0.2204 136878 90.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.59→48.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8632 0 192 864 9688
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.029083
X-RAY DIFFRACTIONf_angle_d1.7312280
X-RAY DIFFRACTIONf_dihedral_angle_d19.8953527
X-RAY DIFFRACTIONf_chiral_restr0.1451285
X-RAY DIFFRACTIONf_plane_restr0.0111544
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5859-1.61320.28362900.30065424X-RAY DIFFRACTION72
1.6132-1.64260.32983270.29266032X-RAY DIFFRACTION81
1.6426-1.67410.29873390.27926140X-RAY DIFFRACTION80
1.6741-1.70830.29373190.27746220X-RAY DIFFRACTION83
1.7083-1.74550.28173600.27266191X-RAY DIFFRACTION81
1.7455-1.78610.30253180.26256203X-RAY DIFFRACTION83
1.7861-1.83070.24633240.25436154X-RAY DIFFRACTION81
1.8307-1.88020.27083070.24766328X-RAY DIFFRACTION84
1.8802-1.93550.27623270.24626294X-RAY DIFFRACTION84
1.9355-1.9980.25593280.23916467X-RAY DIFFRACTION85
1.998-2.06940.27843500.23016434X-RAY DIFFRACTION85
2.0694-2.15220.25733400.23276496X-RAY DIFFRACTION86
2.1522-2.25010.23933480.22256518X-RAY DIFFRACTION86
2.2501-2.36870.2583370.22326774X-RAY DIFFRACTION89
2.3687-2.51710.23113920.21886947X-RAY DIFFRACTION92
2.5171-2.71130.24613840.21136953X-RAY DIFFRACTION92
2.7113-2.98390.24533550.20856918X-RAY DIFFRACTION91
2.9839-3.41520.2243970.19317058X-RAY DIFFRACTION93
3.4152-4.30090.21013600.16947131X-RAY DIFFRACTION93
4.3009-30.50010.2483800.21117271X-RAY DIFFRACTION94

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