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- PDB-4yhf: Bruton's tyrosine kinase in complex with a t-butyl cyanoacrylamid... -

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Basic information

Entry
Database: PDB / ID: 4yhf
TitleBruton's tyrosine kinase in complex with a t-butyl cyanoacrylamide inhibitor
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / Covalent inhibitor / cyanoacrylamide / cysteine
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 / 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-4C9 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsPaavilainen, V.O. / McFarland, J.M. / Taunton, J.
Funding support United States, Finland, 4items
OrganizationGrant numberCountry
National Institutes of HealthGM071434 United States
National Institutes of HealthF32GM087052 United States
Academy of Finland Finland
Sigrid Juselius Foundation Finland
CitationJournal: Nat.Chem.Biol. / Year: 2015
Title: Prolonged and tunable residence time using reversible covalent kinase inhibitors.
Authors: Bradshaw, J.M. / McFarland, J.M. / Paavilainen, V.O. / Bisconte, A. / Tam, D. / Phan, V.T. / Romanov, S. / Finkle, D. / Shu, J. / Patel, V. / Ton, T. / Li, X. / Loughhead, D.G. / Nunn, P.A. ...Authors: Bradshaw, J.M. / McFarland, J.M. / Paavilainen, V.O. / Bisconte, A. / Tam, D. / Phan, V.T. / Romanov, S. / Finkle, D. / Shu, J. / Patel, V. / Ton, T. / Li, X. / Loughhead, D.G. / Nunn, P.A. / Karr, D.E. / Gerritsen, M.E. / Funk, J.O. / Owens, T.D. / Verner, E. / Brameld, K.A. / Hill, R.J. / Goldstein, D.M. / Taunton, J.
History
DepositionFeb 27, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0May 13, 2015Provider: repository / Type: Initial release
Revision 1.1May 27, 2015Group: Database references
Revision 1.2Jun 3, 2015Group: Database references
Revision 1.3Jul 1, 2015Group: Database references
Revision 1.4Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.5Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,17046
Polymers64,5382
Non-polymers2,63244
Water6,684371
1
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,42218
Polymers32,2691
Non-polymers1,15317
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,74828
Polymers32,2691
Non-polymers1,47927
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.770, 77.090, 88.030
Angle α, β, γ (deg.)90.00, 96.43, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 32269.020 Da / Num. of mol.: 2 / Fragment: UNP residues 382-659
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Plasmid: pFASTBAC / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase

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Non-polymers , 6 types, 415 molecules

#2: Chemical ChemComp-4C9 / (2S)-2-({(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}carbonyl)-4,4-dimethylpentanenitrile


Mass: 523.629 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H33N7O2
#3: Chemical...
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: Na
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 371 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.29 Å3/Da / Density % sol: 46.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M MES pH 6.5, 0.2 M (NH4)SO4, and 30% (w/v) PEG 5000 MME

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→38.55 Å / Num. all: 29610 / Num. obs: 29610 / % possible obs: 99.97 % / Redundancy: 4.3 % / Net I/σ(I): 11.8
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 4.3 % / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.8.2_1309)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3GEN

3gen


Resolution: 2.2→38.55 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / Phase error: 20.86 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2079 2000 6.76 %Random selection
Rwork0.1738 ---
obs0.1762 29604 99.95 %-
Solvent computationShrinkage radii: 1.1 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→38.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4145 0 156 371 4672
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044423
X-RAY DIFFRACTIONf_angle_d0.8485986
X-RAY DIFFRACTIONf_dihedral_angle_d13.6841603
X-RAY DIFFRACTIONf_chiral_restr0.049623
X-RAY DIFFRACTIONf_plane_restr0.003757
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.25510.25211400.22851937X-RAY DIFFRACTION100
2.2551-2.3160.27721410.2041950X-RAY DIFFRACTION100
2.316-2.38420.2471430.19371974X-RAY DIFFRACTION100
2.3842-2.46110.26131430.19021967X-RAY DIFFRACTION100
2.4611-2.5490.22871420.18761964X-RAY DIFFRACTION100
2.549-2.65110.24521420.18561953X-RAY DIFFRACTION100
2.6511-2.77170.23341440.18761992X-RAY DIFFRACTION100
2.7717-2.91780.25571430.18361977X-RAY DIFFRACTION100
2.9178-3.10050.19241420.17851940X-RAY DIFFRACTION100
3.1005-3.33980.1891420.17371983X-RAY DIFFRACTION100
3.3398-3.67560.17721450.15931996X-RAY DIFFRACTION100
3.6756-4.2070.19131420.14391955X-RAY DIFFRACTION100
4.207-5.29810.16831440.14811987X-RAY DIFFRACTION100
5.2981-38.55090.19471470.18572029X-RAY DIFFRACTION100

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