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- PDB-6hrp: CRYSTAL STRUCTURE OF BTK KINASE DOMAIN COMPLEXED WITH 6-(dimethyl... -

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Basic information

Entry
Database: PDB / ID: 6hrp
TitleCRYSTAL STRUCTURE OF BTK KINASE DOMAIN COMPLEXED WITH 6-(dimethylamino)-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]-3,4-dihydroisoquinolin-1-one
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / 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 / eosinophil homeostasis / regulation of B cell apoptotic process / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / positive regulation of cGAS/STING signaling pathway ...regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / regulation of B cell apoptotic process / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / positive regulation of cGAS/STING signaling pathway / histamine secretion by mast cell / neutrophil homeostasis / 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 immunoglobulin production / positive regulation of B cell differentiation / 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 / phospholipase binding / B cell activation / phosphatidylinositol-3,4,5-trisphosphate binding / RHO GTPases Activate WASPs and WAVEs / positive regulation of phagocytosis / cell maturation / positive regulation of B cell proliferation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / cellular response to reactive oxygen species / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / apoptotic signaling pathway / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / calcium-mediated signaling / peptidyl-tyrosine phosphorylation / 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 / G alpha (12/13) signalling events / DAP12 signaling / T cell receptor signaling pathway / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / protein tyrosine kinase activity / cytoplasmic vesicle / G alpha (q) signalling events / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / response to lipopolysaccharide / adaptive immune response / Potential therapeutics for SARS / intracellular signal transduction / protein phosphorylation / membrane raft / 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 ...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-GMQ / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.12 Å
AuthorsJanson, C. / Kuglstatter, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: A potent seven-membered cyclic BTK (Bruton's tyrosine Kinase) chiral inhibitor conceived by structure-based drug design to lock its bioactive conformation.
Authors: Lopez-Tapia, F. / Lou, Y. / Brotherton-Pleiss, C. / Kuglstatter, A. / So, S.S. / Kondru, R.
History
DepositionSep 28, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2May 15, 2019Group: Data collection / Refinement description / Category: pdbx_refine_tls_group
Item: _pdbx_refine_tls_group.beg_auth_seq_id / _pdbx_refine_tls_group.end_auth_asym_id / _pdbx_refine_tls_group.end_auth_seq_id
Revision 1.3May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)33,1612
Polymers32,5211
Non-polymers6401
Water7,999444
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.805, 106.969, 38.299
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 32521.135 Da / Num. of mol.: 1 / Mutation: M489A, R492A, E624A, K625A
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-GMQ / 6-~{tert}-butyl-8-fluoranyl-2-[2-(hydroxymethyl)-3-[1-methyl-5-[(5-morpholin-4-ylcarbonylpyridin-2-yl)amino]-6-oxidanylidene-pyridazin-3-yl]phenyl]phthalazin-1-one


Mass: 639.676 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H34FN7O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 444 / 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: 2.26 Å3/Da / Density % sol: 45.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 33% PEG3350, 0.1M HEPES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 2, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.12→42.87 Å / Num. obs: 112605 / % possible obs: 99.1 % / Redundancy: 6.2 % / Rmerge(I) obs: 0.047 / Net I/σ(I): 16.9
Reflection shellResolution: 1.12→1.18 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.482 / Mean I/σ(I) obs: 2.8 / Num. unique obs: 15523 / % possible all: 94.9

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Processing

Software
NameVersionClassification
REFMAC5.5.0072refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.12→38.3 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.965 / SU B: 1.075 / SU ML: 0.024 / Cross valid method: THROUGHOUT / ESU R: 0.033 / ESU R Free: 0.035
RfactorNum. reflection% reflectionSelection details
Rfree0.19243 5620 5 %RANDOM
Rwork0.17391 ---
obs0.17486 106475 98.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso mean: 15.453 Å2
Baniso -1Baniso -2Baniso -3
1-0.61 Å20 Å20 Å2
2--0.06 Å20 Å2
3----0.66 Å2
Refinement stepCycle: 1 / Resolution: 1.12→38.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2139 0 47 444 2630
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0260.0222241
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.0841.9863030
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2985262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.74624.135104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.66315401
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9911512
X-RAY DIFFRACTIONr_chiral_restr0.1240.2316
X-RAY DIFFRACTIONr_gen_planes_refined0.0150.0211716
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.251.51309
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.11422111
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.0933932
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.8814.5919
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.122→1.151 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 365 -
Rwork0.348 6943 -
obs--88.27 %
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)
10.00230.00690.01031.21620.01510.0466-0.0022-0.0024-0.0088-0.04310.04980.02550.0287-0.0119-0.04750.0442-0.0111-0.01140.00620.01130.043319.2566-1.94477.508
20.12120.0259-0.0470.0696-0.0570.36070.0037-0.01360.015-0.01080.0120.0066-0.0209-0.0051-0.01570.00670.00070.0010.01220.00030.003218.427327.52322.5894
30.9602-0.12150.79491.0125-1.27832.06160.0326-0.0854-0.1844-0.01290.11610.01770.0685-0.2114-0.14870.0561-0.01950.00310.02460.01280.037616.46285.403919.9629
40.53490.54750.91321.34021.50821.9895-0.04650.0441-0.00990.0120.1099-0.0927-0.01790.1222-0.06340.0432-0.00070.02390.0092-0.00930.033629.14675.5167.3174
50.0394-0.02270.08880.1168-0.17340.3529-0.0025-0.0077-0.0041-0.0074-0.0023-0.00810.0143-0.00270.00470.01380.0040.00170.01320.00450.002421.611615.642610.7426
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 407
2X-RAY DIFFRACTION1A453 - 476
3X-RAY DIFFRACTION1A418 - 436
4X-RAY DIFFRACTION2A477 - 514
5X-RAY DIFFRACTION2A559 - 1000
6X-RAY DIFFRACTION3A437 - 452
7X-RAY DIFFRACTION4A408 - 417
8X-RAY DIFFRACTION5A515 - 558

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