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- PDB-4xi2: Crystal Structure of an auto-inhibited form of Bruton's Tryrosine... -

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Basic information

Entry
Database: PDB / ID: 4xi2
TitleCrystal Structure of an auto-inhibited form of Bruton's Tryrosine Kinase
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / Kinase / Phosphorylation / Auto-inhibited / B-Cell development / X-linked agammaglobulinemia
Function / homology
Function and homology information


negative regulation of B cell activation / G beta:gamma signalling through BTK / RHO GTPases Activate WASPs and WAVEs / FCERI mediated Ca+2 mobilization / G alpha (q) signalling events / G alpha (12/13) signalling events / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of actin dynamics for phagocytic cup formation / proteoglycan catabolic process / monocyte proliferation ...negative regulation of B cell activation / G beta:gamma signalling through BTK / RHO GTPases Activate WASPs and WAVEs / FCERI mediated Ca+2 mobilization / G alpha (q) signalling events / G alpha (12/13) signalling events / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of actin dynamics for phagocytic cup formation / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / histamine secretion by mast cell / positive regulation of synoviocyte proliferation / negative regulation of leukocyte proliferation / neutrophil homeostasis / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / cellular response to interleukin-7 / DAP12 signaling / negative regulation of cytokine production / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / positive regulation of immunoglobulin production / positive regulation of phagocytosis / positive regulation of B cell proliferation / cell maturation / response to organic substance / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cellular response to reactive oxygen species / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / T cell receptor signaling pathway / cytoplasmic vesicle / protein tyrosine kinase activity / response to lipopolysaccharide / adaptive immune response / intracellular signal transduction / membrane raft / phosphorylation / innate immune response / apoptotic process / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.6 Å
AuthorsVogan, E.M. / Harrison, S.C.
CitationJournal: Elife / Year: 2015
Title: Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate.
Authors: Wang, Q. / Vogan, E.M. / Nocka, L.M. / Rosen, C.E. / Zorn, J.A. / Harrison, S.C. / Kuriyan, J.
History
DepositionJan 6, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 25, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 11, 2015Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_prerelease_seq / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation

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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)52,1933
Polymers51,7991
Non-polymers3942
Water0
1
A: Tyrosine-protein kinase BTK
hetero molecules

A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)104,3866
Polymers103,5982
Non-polymers7884
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556y,x,-z+11
Buried area8530 Å2
ΔGint-77 kcal/mol
Surface area42280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)132.202, 132.202, 107.632
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121
DetailsThe biological unit is split across the asymmetric unit (domain-swapped dimer). Authors believe that the biological assembly is a crystallographic artifact, and is unrelated to the functional state of the protein in the cell.

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Components

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


Mass: 51798.816 Da / Num. of mol.: 1 / Fragment: UNP residues 214-659
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Btk, Bpk / Plasmid: Bac-to-Bac / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf21
References: UniProt: P35991, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-AU / GOLD ION


Mass: 196.967 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Au

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 5.411 Å3/Da / Density % sol: 77.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: Mix purified dimer protein at 5 mg/ml in 25 mM TRIS.Cl, pH 8.5, 10 mM NaCl, 5 mM DTT with an equal volume of the precipitant solution, 100 mM TRIS.Cl, pH 8.5, 200 mM Na.acetate, 7.5 % PEG ...Details: Mix purified dimer protein at 5 mg/ml in 25 mM TRIS.Cl, pH 8.5, 10 mM NaCl, 5 mM DTT with an equal volume of the precipitant solution, 100 mM TRIS.Cl, pH 8.5, 200 mM Na.acetate, 7.5 % PEG 4,000, then suspend over 1 ml of precipitant solution. Wedge shaped crystals grew to approximately 0.1 mm on a side after a period of two weeks. Crystals were frozen by first transferring them, in four sequential steps, to a solution of 100 mM TRIS.Cl, pH 8.5, 200 mM Na.acetate, 15 % PEG 4,000. This was followed by transfer in six sequential steps to a solution containing 100 mM TRIS.Cl, pH 8.5, 200 mM Na.acetate, 15 % PEG 4,000, 30% glucose

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: A1 / Wavelength: 0.9474 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 2, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9474 Å / Relative weight: 1
ReflectionResolution: 2.6→43.3 Å / Num. obs: 30976 / % possible obs: 91.9 % / Redundancy: 4.8 % / Biso Wilson estimate: 72.8 Å2 / Rsym value: 0.087 / Net I/σ(I): 10.6
Reflection shellResolution: 2.6→2.66 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 1.1 / % possible all: 69.6

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: dev_1839)refinement
DENZO1.97.8data reduction
SCALEPACK1.97.7data scaling
SHARP1.4phasing
RefinementResolution: 2.6→43.273 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / Phase error: 30.1 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2483 2830 4.91 %random
Rwork0.2296 ---
obs0.2306 30931 89.22 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 114.4 Å2
Refinement stepCycle: LAST / Resolution: 2.6→43.273 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3459 0 2 0 3461
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073541
X-RAY DIFFRACTIONf_angle_d1.1144776
X-RAY DIFFRACTIONf_dihedral_angle_d17.4011321
X-RAY DIFFRACTIONf_chiral_restr0.052501
X-RAY DIFFRACTIONf_plane_restr0.005606
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.64610.3433960.37251731X-RAY DIFFRACTION58
2.6461-2.69430.43711130.37112084X-RAY DIFFRACTION67
2.6943-2.74610.46061080.34582281X-RAY DIFFRACTION73
2.7461-2.80210.3918910.3322481X-RAY DIFFRACTION81
2.8021-2.8630.35531440.33032708X-RAY DIFFRACTION89
2.863-2.92960.35541290.31192856X-RAY DIFFRACTION92
2.9296-3.00290.3451280.30712937X-RAY DIFFRACTION95
3.0029-3.0840.32281410.28942946X-RAY DIFFRACTION96
3.084-3.17470.30791570.26152914X-RAY DIFFRACTION95
3.1747-3.27720.24411380.24152950X-RAY DIFFRACTION95
3.2772-3.39430.2331880.23132915X-RAY DIFFRACTION96
3.3943-3.53010.23881350.21762934X-RAY DIFFRACTION96
3.5301-3.69070.2321740.21722913X-RAY DIFFRACTION95
3.6907-3.88520.2481530.21012946X-RAY DIFFRACTION95
3.8852-4.12840.25361750.20472856X-RAY DIFFRACTION95
4.1284-4.44690.23861550.19432863X-RAY DIFFRACTION95
4.4469-4.89380.21371580.1922959X-RAY DIFFRACTION95
4.8938-5.60070.22991340.21532874X-RAY DIFFRACTION94
5.6007-7.05130.22711500.24292877X-RAY DIFFRACTION93
7.0513-43.27920.21381630.21752789X-RAY DIFFRACTION91
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)
10.34420.06290.10190.98630.18730.9568-0.1683-0.213-0.11820.8030.154-0.7643-0.37490.27880.00071.09410.2325-0.14030.7556-0.07410.750722.294263.471516.694
2-0.922-0.54181.9608-3.0301-1.16311.45870.0515-0.5914-0.15290.2199-0.1051-0.2413-0.34850.19240.10172.3318-0.1493-0.35612.11830.07281.316131.321763.874349.9921
33.95611.5884-1.48232.354-0.93793.153-0.0071-0.83920.00920.28680.03360.26460.0617-0.1726-0.00010.49860.0029-0.00210.84990.01350.790874.497358.711484.7769
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 214:260 )A214 - 260
2X-RAY DIFFRACTION2( CHAIN A AND RESID 261:391 )A261 - 391
3X-RAY DIFFRACTION3( CHAIN A AND RESID 392:657 )A392 - 657

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