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- PDB-9me3: Bruton's tyrosine kinase with mutations in the activation loop in... -

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Basic information

Entry
Database: PDB / ID: 9me3
TitleBruton's tyrosine kinase with mutations in the activation loop in complex with compound P301390
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / inhibitor / kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRANSFERASE
Function / homology
Function and homology information


G beta:gamma signalling through BTK / RHO GTPases Activate WASPs and WAVEs / G alpha (12/13) signalling events / FCERI mediated Ca+2 mobilization / G alpha (q) signalling events / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / monocyte proliferation / positive regulation of interleukin-17A production / Regulation of actin dynamics for phagocytic cup formation / eosinophil homeostasis ...G beta:gamma signalling through BTK / RHO GTPases Activate WASPs and WAVEs / G alpha (12/13) signalling events / FCERI mediated Ca+2 mobilization / G alpha (q) signalling events / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / monocyte proliferation / positive regulation of interleukin-17A production / Regulation of actin dynamics for phagocytic cup formation / eosinophil homeostasis / proteoglycan catabolic process / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / positive regulation of cGAS/STING signaling pathway / 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 immunoglobulin production / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / positive regulation of NLRP3 inflammasome complex assembly / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / cell maturation / positive regulation of B cell proliferation / positive regulation of phagocytosis / cellular response to reactive oxygen species / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / cytoplasmic vesicle / protein tyrosine kinase activity / response to lipopolysaccharide / intracellular signal transduction / membrane raft / innate immune response / apoptotic process / perinuclear region of cytoplasm / zinc ion binding / ATP binding / identical protein 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 ...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 / 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 / MOLECULAR REPLACEMENT / Resolution: 3.05 Å
AuthorsLin, D.Y. / Andreotti, A.H. / Tonge, P.J. / Bravo, E. / Li, X.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: J.Am.Chem.Soc. / Year: 2025
Title: Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects
Authors: Bravo, E.J. / Li, Y. / Lin, D.Y.W. / Srinivasan, B. / Barone, M. / Li, S.X. / DelloRusso, F. / Rahiyanath, A.S. / Corrionero, A. / Alfonso, P. / Prendiville, N. / Kozakov, D. / Andreotti, A.H. / Tonge, P.J.
History
DepositionDec 6, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release

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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)32,1252
Polymers31,8221
Non-polymers3031
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)107.630, 107.630, 45.276
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61
Space group name HallP61
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z+1/2

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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: 31821.521 Da / Num. of mol.: 1
Mutation: K430R, L542M, S543T, V555T, R562K, S564A, P565S,Y617P
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Btk, Bpk / Production host: Escherichia coli (E. coli)
References: UniProt: P35991, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-A1BJE / 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 303.318 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H13N5O
Has ligand of interestY
Has protein modificationN

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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: 2.38 Å3/Da / Density % sol: 48.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Sodium citrate tribasic dihydrate pH 5.5, 18% w/v Polyethylene glycol 8,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X17B1 / Wavelength: 0.920153 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 25, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.920153 Å / Relative weight: 1
ReflectionResolution: 3.048→34.646 Å / Num. obs: 5760 / % possible obs: 98.4 % / Redundancy: 42.4 % / Biso Wilson estimate: 84.74 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.277 / Rpim(I) all: 0.043 / Rrim(I) all: 0.28 / Net I/σ(I): 13
Reflection shellResolution: 3.048→3.116 Å / Redundancy: 22.1 % / Rmerge(I) obs: 0.2737 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 289 / CC1/2: 0.428 / Rpim(I) all: 0.07223 / Rrim(I) all: 0.2833 / % possible all: 81.4

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.05→19.34 Å / SU ML: 0.2226 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 34.3407
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2879 304 5.28 %
Rwork0.2248 5454 -
obs0.2281 5758 98.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 84.88 Å2
Refinement stepCycle: LAST / Resolution: 3.05→19.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2111 0 23 0 2134
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00432193
X-RAY DIFFRACTIONf_angle_d0.94582965
X-RAY DIFFRACTIONf_chiral_restr0.053318
X-RAY DIFFRACTIONf_plane_restr0.0075376
X-RAY DIFFRACTIONf_dihedral_angle_d15.1905801
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.05-3.160.357320.3667464X-RAY DIFFRACTION84.5
3.16-3.280.4512320.3556535X-RAY DIFFRACTION99.1
3.28-3.430.3779270.3354558X-RAY DIFFRACTION100
3.43-3.610.3989320.2904541X-RAY DIFFRACTION100
3.61-3.830.3384170.2827567X-RAY DIFFRACTION100
3.84-4.120.2856450.2454537X-RAY DIFFRACTION100
4.13-4.540.2613450.2065537X-RAY DIFFRACTION100
4.54-5.180.2775310.1965555X-RAY DIFFRACTION100
5.19-6.480.2813310.1837565X-RAY DIFFRACTION100
6.49-19.340.216330.1581575X-RAY DIFFRACTION99.3
Refinement TLS params.Method: refined / Origin x: 34.9168913128 Å / Origin y: -21.1878322409 Å / Origin z: -1.30129423201 Å
111213212223313233
T0.495033700779 Å20.0362006860361 Å2-0.0985812524178 Å2-0.448752930454 Å2-0.102358529953 Å2--0.426566995818 Å2
L4.05605706287 °20.618144330694 °21.29697053692 °2-3.96736133453 °20.712770105942 °2--3.63233503844 °2
S-0.43264650989 Å °-0.0727172995486 Å °0.35812454441 Å °-0.138952151327 Å °-0.102841500385 Å °-0.143207790075 Å °-0.50899658552 Å °-0.173839015407 Å °0.496385699921 Å °
Refinement TLS groupSelection details: all

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