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- PDB-7i9d: Crystal Structure of 14 bound to the PH domain of Btk -

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Basic information

Entry
Database: PDB / ID: 7i9d
TitleCrystal Structure of 14 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 / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell ...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 / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / positive regulation of cGAS/STING signaling pathway / neutrophil homeostasis / positive regulation of type I hypersensitivity / cellular response to molecule of fungal origin / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / negative regulation of interleukin-10 production / MyD88-dependent toll-like receptor signaling pathway / positive regulation of B cell differentiation / phospholipase activator activity / negative regulation of B cell proliferation / positive regulation of immunoglobulin production / Fc-epsilon receptor signaling pathway / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of NLRP3 inflammasome complex assembly / B cell activation / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / cell maturation / positive regulation of B cell proliferation / peptidyl-tyrosine phosphorylation / : / FCERI mediated Ca+2 mobilization / positive regulation of phagocytosis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / B cell receptor signaling pathway / calcium-mediated signaling / apoptotic signaling pathway / 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 / positive regulation of tumor necrosis factor production / G beta:gamma signalling through BTK / DAP12 signaling / T cell receptor signaling pathway / G alpha (12/13) signalling events / ER-Phagosome pathway / protein tyrosine kinase activity / cytoplasmic vesicle / response to lipopolysaccharide / 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 / 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: 1.8 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
DepositionMar 24, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2026Provider: repository / Type: Initial release
Revision 1.1Jun 24, 2026Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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
C: Tyrosine-protein kinase BTK
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,03115
Polymers79,8684
Non-polymers1,16311
Water3,657203
1
A: Tyrosine-protein kinase BTK
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6538
Polymers39,9342
Non-polymers7196
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2540 Å2
ΔGint-27 kcal/mol
Surface area17250 Å2
MethodPISA
2
C: Tyrosine-protein kinase BTK
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3787
Polymers39,9342
Non-polymers4445
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2660 Å2
ΔGint-26 kcal/mol
Surface area16870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.515, 66.600, 79.634
Angle α, β, γ (deg.)90.00, 101.09, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#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 / 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

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Non-polymers , 5 types, 214 molecules

#2: Chemical ChemComp-A1B6M / [(3S,3aS,6S,7aR)-6-(2-hydroxyphenyl)octahydro-1-benzofuran-3-yl]methanediol


Mass: 264.317 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C15H20O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 44.9 %
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
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: May 29, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.8→67.23 Å / Num. obs: 65293 / % possible obs: 99.9 % / Redundancy: 6.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.027 / Rrim(I) all: 0.072 / Net I/σ(I): 15.8 / Num. measured all: 452977
Reflection shellResolution: 1.8→1.83 Å / % possible obs: 98.2 % / Redundancy: 7 % / Rmerge(I) obs: 3.265 / Num. measured all: 22089 / Num. unique obs: 3144 / CC1/2: 0.34 / Rpim(I) all: 1.318 / Rrim(I) all: 3.525 / Net I/σ(I) obs: 0.3

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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: 1.8→67.23 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.913 / SU R Cruickshank DPI: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.155 / SU Rfree Blow DPI: 0.153 / SU Rfree Cruickshank DPI: 0.157
RfactorNum. reflection% reflectionSelection details
Rfree0.2974 3271 5.05 %RANDOM
Rwork0.2448 ---
obs0.2475 64777 99.2 %-
Displacement parametersBiso mean: 56.09 Å2
Baniso -1Baniso -2Baniso -3
1--11.4643 Å20 Å20.6314 Å2
2--3.3636 Å20 Å2
3---8.1007 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: LAST / Resolution: 1.8→67.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5274 0 65 205 5544
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0095478HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.017397HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1983SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes898HARMONIC5
X-RAY DIFFRACTIONt_it5478HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.76
X-RAY DIFFRACTIONt_other_torsion19.07
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion680SEMIHARMONIC5
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_contact4145SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.81 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.4492 65 4.86 %
Rwork0.4422 1233 -
all0.4425 1296 -
obs--82.69 %

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