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- PDB-9rn5: Crystal Structure of 33 bound to the PH domain of Btk -

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Basic information

Entry
Database: PDB / ID: 9rn5
TitleCrystal Structure of 33 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: 1.83 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 19, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 12, 2026Provider: 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
B: Tyrosine-protein kinase BTK
C: Tyrosine-protein kinase BTK
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,38214
Polymers79,8044
Non-polymers1,57810
Water3,153175
1
A: Tyrosine-protein kinase BTK
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7117
Polymers39,9022
Non-polymers8105
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2330 Å2
ΔGint-19 kcal/mol
Surface area16980 Å2
2
C: Tyrosine-protein kinase BTK
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6707
Polymers39,9022
Non-polymers7685
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2130 Å2
ΔGint-21 kcal/mol
Surface area16560 Å2
Unit cell
Length a, b, c (Å)68.979, 67.148, 79.776
Angle α, β, γ (deg.)90.000, 100.579, 90.000
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: 19950.949 Da / Num. of mol.: 4 / Fragment: PH DOMAIN AND BTK MOTIF
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-A1JR3 / (6S)-6-(4-bromanylthiophen-2-yl)-4,5,6,7-tetrahydro-1-benzofuran-3-carboxylic acid


Mass: 327.194 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H11BrO3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 175 / 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: 2.28 Å3/Da / Density % sol: 45.95 %
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: I04 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Mar 13, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.83→51 Å / Num. obs: 63456 / % possible obs: 99.8 % / Redundancy: 6.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.043 / Rrim(I) all: 0.114 / Net I/σ(I): 10.3 / Num. measured all: 439862
Reflection shellResolution: 1.83→1.86 Å / % possible obs: 98.1 % / Redundancy: 7.1 % / Rmerge(I) obs: 3.406 / Num. measured all: 22282 / Num. unique obs: 3134 / CC1/2: 0.573 / Rpim(I) all: 1.366 / Rrim(I) all: 3.673 / Net I/σ(I) obs: 0.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0430refinement
DIALSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.83→51 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.914 / SU B: 0.01 / SU ML: 0 / Cross valid method: THROUGHOUT / ESU R: 0.182 / ESU R Free: 0.198
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.3503 3105 4.962 %RANDOM
Rwork0.3208 59475 --
all0.322 ---
obs-62580 98.444 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 53.279 Å2
Baniso -1Baniso -2Baniso -3
1-2.242 Å20 Å20.229 Å2
2--1.625 Å20 Å2
3----3.694 Å2
Refinement stepCycle: LAST / Resolution: 1.83→51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5188 0 78 175 5441
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.83-1.8750.631820.6273711X-RAY DIFFRACTION83.1127
1.875-1.9270.6022080.5774243X-RAY DIFFRACTION97.3748
1.927-1.9830.562230.5344157X-RAY DIFFRACTION99.3423
1.983-2.0430.4942280.4774082X-RAY DIFFRACTION99.6993
2.043-2.110.4322270.4553903X-RAY DIFFRACTION99.8308
2.11-2.1840.4582290.4313801X-RAY DIFFRACTION99.8513
2.184-2.2670.4991890.4373696X-RAY DIFFRACTION99.8715
2.267-2.3590.4391810.4253580X-RAY DIFFRACTION100
2.359-2.4640.3881920.4133416X-RAY DIFFRACTION99.9446
2.464-2.5840.3371680.4023264X-RAY DIFFRACTION100
2.584-2.7230.3991620.3953123X-RAY DIFFRACTION100
2.723-2.8880.4211410.3812971X-RAY DIFFRACTION100
2.888-3.0860.3731390.3532787X-RAY DIFFRACTION100
3.086-3.3330.3881360.3262594X-RAY DIFFRACTION100
3.333-3.6490.31250.2832380X-RAY DIFFRACTION100
3.649-4.0770.2781110.2482164X-RAY DIFFRACTION100
4.077-4.7030.243860.2141935X-RAY DIFFRACTION100
4.703-5.7480.294770.2071647X-RAY DIFFRACTION100
5.748-8.0770.277540.2621287X-RAY DIFFRACTION100
8.077-510.306470.275734X-RAY DIFFRACTION100

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