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- PDB-9rl9: Crystal Structure of 24 bound to the PH domain of Btk -

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Basic information

Entry
Database: PDB / ID: 9rl9
TitleCrystal Structure of 24 bound to the PH domain of Btk
ComponentsTyrosine-protein kinase BTK
KeywordsHYDROLASE / Fragment based drug discovery / ph domain
Function / homology
Function and homology information


regulation of B cell cytokine production / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / proteoglycan catabolic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / negative regulation of B cell activation / positive regulation of synoviocyte proliferation / neutrophil homeostasis ...regulation of B cell cytokine production / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / proteoglycan catabolic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / negative regulation of B cell activation / positive regulation of synoviocyte proliferation / neutrophil homeostasis / histamine secretion by mast cell / negative regulation of leukocyte proliferation / positive regulation of type I hypersensitivity / positive regulation of cGAS/STING signaling pathway / cellular response to molecule of fungal origin / MyD88 deficiency (TLR2/4) / IRAK4 deficiency (TLR2/4) / negative regulation of interleukin-10 production / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / MyD88-dependent toll-like receptor signaling pathway / phospholipase activator activity / positive regulation of immunoglobulin production / mesoderm development / Fc-epsilon receptor signaling pathway / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of NLRP3 inflammasome complex assembly / B cell activation / positive regulation of B cell proliferation / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / peptidyl-tyrosine phosphorylation / FCERI mediated Ca+2 mobilization / B cell receptor signaling pathway / positive regulation of phagocytosis / apoptotic signaling pathway / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calcium-mediated signaling / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / cellular response to reactive oxygen species / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / T cell receptor signaling pathway / positive regulation of tumor necrosis factor production / G beta:gamma signalling through BTK / DAP12 signaling / G alpha (12/13) signalling events / response to lipopolysaccharide / ER-Phagosome pathway / protein tyrosine kinase activity / cytoplasmic vesicle / Potential therapeutics for SARS / G alpha (q) signalling events / adaptive immune response / positive regulation of canonical NF-kappaB signal transduction / intracellular signal transduction / membrane raft / innate immune response / perinuclear region of cytoplasm / DNA-templated transcription / 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 / 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 speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å
AuthorsBrear, P. / West, R.M. / Nicolescu, R.C.B. / Blaszczyk, B.K. / Anwar, A. / Deingruber, T. / Sanders, M.G. / Perez-Areales, F.J. / Stephens, L.R. / Hawkins, P.T. ...Brear, P. / West, R.M. / Nicolescu, R.C.B. / Blaszczyk, B.K. / Anwar, A. / Deingruber, T. / Sanders, M.G. / Perez-Areales, F.J. / Stephens, L.R. / Hawkins, P.T. / Spring, D.R. / Hyvonen, M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other private United Kingdom
CitationJournal: J.Med.Chem. / Year: 2026
Title: Targeting a Pleckstrin Homology Domain with a Lysine-Reactive Covalent Binder.
Authors: West, R.M. / Bizga Nicolescu, R.C. / Brear, P. / Wagstaff, J. / Blaszczyk, B.K. / Deingruber, T. / Sanders, M.G. / Perez-Areales, F.J. / Spring, D.R. / Hyvonen, M.
History
DepositionJun 16, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 20, 2026Provider: repository / Type: Initial release
Revision 1.1Jun 3, 2026Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jul 29, 2026Group: Structure summary / Category: pdbx_deposit_group

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)81,33416
Polymers79,8684
Non-polymers1,46612
Water2,522140
1
A: Tyrosine-protein kinase BTK
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6678
Polymers39,9342
Non-polymers7336
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2680 Å2
ΔGint-26 kcal/mol
Surface area17960 Å2
2
C: Tyrosine-protein kinase BTK
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6678
Polymers39,9342
Non-polymers7336
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2820 Å2
ΔGint-30 kcal/mol
Surface area17580 Å2
Unit cell
Length a, b, c (Å)68.344, 66.376, 79.701
Angle α, β, γ (deg.)90.00, 100.25, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 19966.949 Da / Num. of mol.: 4 / Fragment: PH DOMAIN AND BTK MOTIF / Mutation: C145S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-A1B6R / (6S)-6-(4-chlorophenyl)-4,5,6,7-tetrahydro-1-benzofuran-3-carboxylic acid


Mass: 276.715 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C15H13ClO3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 140 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.23 Å3/Da / Density % sol: 44.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M TRIS, 32.5% w/v PEG 3350, 200mM MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Mar 14, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.11→56.24 Å / Num. obs: 40587 / % possible obs: 99.9 % / Redundancy: 7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.123 / Rpim(I) all: 0.05 / Rrim(I) all: 0.133 / Net I/σ(I): 10.3 / Num. measured all: 284078
Reflection shellResolution: 2.11→2.15 Å / % possible obs: 99.3 % / Redundancy: 7.2 % / Rmerge(I) obs: 2.709 / Num. measured all: 14307 / Num. unique obs: 1998 / CC1/2: 0.311 / Rpim(I) all: 1.088 / Rrim(I) all: 2.922 / Net I/σ(I) obs: 0.4

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (10-JUL-2024)refinement
DIALSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.11→30.56 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.875 / SU R Cruickshank DPI: 0.323 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.31 / SU Rfree Blow DPI: 0.259 / SU Rfree Cruickshank DPI: 0.266
RfactorNum. reflection% reflectionSelection details
Rfree0.3329 2029 5.01 %RANDOM
Rwork0.2624 ---
obs0.266 40484 99.7 %-
Displacement parametersBiso mean: 69.12 Å2
Baniso -1Baniso -2Baniso -3
1--14.0639 Å20 Å2-2.1995 Å2
2--3.0169 Å20 Å2
3---11.0471 Å2
Refine analyzeLuzzati coordinate error obs: 0.41 Å
Refinement stepCycle: LAST / Resolution: 2.11→30.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5552 0 76 140 5768
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0085857HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.017920HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2178SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes981HARMONIC5
X-RAY DIFFRACTIONt_it5857HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.3
X-RAY DIFFRACTIONt_other_torsion19.73
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion720SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4300SEMIHARMONIC4
LS refinement shellResolution: 2.11→2.12 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.5726 37 4.57 %
Rwork0.4373 773 -
all0.4434 810 -
obs--97.87 %

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