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

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Basic information

Entry
Database: PDB / ID: 9ejs
TitleBruton's tyrosine kinase with mutations in the activation loop in complex with compound PTI52
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / inhibitor / kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / positive regulation of immunoglobulin production / negative regulation of cytokine 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 / cytoplasm / cytosol
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: 2.26 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 Jr., E. / Li, Y. / Lin, D.Y. / 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
DepositionNov 28, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release
Revision 1.1Aug 20, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)97,1107
Polymers95,4653
Non-polymers1,6464
Water4,972276
1
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3442
Polymers31,8221
Non-polymers5231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3442
Polymers31,8221
Non-polymers5231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4223
Polymers31,8221
Non-polymers6012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)106.632, 44.135, 108.002
Angle α, β, γ (deg.)90.000, 117.612, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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.: 3 / Mutation: K430R, L542M, S543T, V555T, R562K, S564A, P565S
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-A1BI0 / 4-{4-amino-1-[(3R)-1-(cyclopropanecarbonyl)piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-(4-cyclopropylpyridin-2-yl)benzamide


Mass: 522.601 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C29H30N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 276 / Source method: isolated from a natural source / Formula: H2O
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: 2.36 Å3/Da / Density % sol: 47.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: Sodium citrate tribasic dihydrate pH 5.5, 16% 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: 2.26→34.16 Å / Num. obs: 32319 / % possible obs: 65.3 % / Redundancy: 5.2 % / Biso Wilson estimate: 28.93 Å2 / CC1/2: 0.976 / CC star: 0.994 / Net I/σ(I): 4.25
Reflection shellResolution: 2.26→2.35 Å / Redundancy: 5.4 % / Rmerge(I) obs: 1.653 / Mean I/σ(I) obs: 0.86 / Num. unique obs: 3542 / CC1/2: 0.33 / CC star: 0.705 / R split: 0.7809 / Rrim(I) all: 1.835 / % possible all: 2.49

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→19.99 Å / SU ML: 0.2929 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.0443
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2463 1309 4.71 %
Rwork0.1908 26502 -
obs0.1935 27811 65.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.98 Å2
Refinement stepCycle: LAST / Resolution: 2.26→19.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6387 0 121 276 6784
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00266682
X-RAY DIFFRACTIONf_angle_d0.50829023
X-RAY DIFFRACTIONf_chiral_restr0.0393960
X-RAY DIFFRACTIONf_plane_restr0.00481133
X-RAY DIFFRACTIONf_dihedral_angle_d15.79032489
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.26-2.350.216960.2461111X-RAY DIFFRACTION2.49
2.35-2.450.3792370.2827661X-RAY DIFFRACTION14.87
2.45-2.580.3033780.2951606X-RAY DIFFRACTION35.95
2.58-2.740.30481610.28522489X-RAY DIFFRACTION56.52
2.74-2.950.38111320.26723435X-RAY DIFFRACTION75.8
2.95-3.250.29912320.24224424X-RAY DIFFRACTION99.19
3.25-3.720.23792500.18494517X-RAY DIFFRACTION100
3.72-4.670.20962100.14234556X-RAY DIFFRACTION100
4.67-19.990.19282030.15544703X-RAY DIFFRACTION99.88
Refinement TLS params.Method: refined / Origin x: -54.5257340045 Å / Origin y: -8.76786422864 Å / Origin z: -31.4280768202 Å
111213212223313233
T0.181393713515 Å20.00152731798478 Å20.0127105664683 Å2-0.121589987258 Å2-0.0292874350634 Å2--0.146033095363 Å2
L0.248560197627 °20.105877900725 °2-0.080400671177 °2-0.399681984919 °2-0.422894186417 °2--0.726545200829 °2
S-0.0414029730413 Å °-0.000584256301206 Å °0.0288475426542 Å °-0.0799038895106 Å °0.0815005034936 Å °0.0221733073667 Å °-0.0510476761653 Å °-0.0785055637628 Å °-0.0371078238414 Å °
Refinement TLS groupSelection details: all

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