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- PDB-9t0t: Crystal Structure of the correct enantiomer bound to the PH domai... -

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Basic information

Entry
Database: PDB / ID: 9t0t
TitleCrystal Structure of the correct enantiomer 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 / MyD88-dependent toll-like receptor signaling pathway / positive regulation of B cell differentiation / phospholipase activator activity / negative regulation of interleukin-10 production / positive regulation of immunoglobulin production / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / mesoderm development / positive regulation of NLRP3 inflammasome complex assembly / phosphatidylinositol-3,4,5-trisphosphate binding / B cell activation / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / positive regulation of B cell proliferation / peptidyl-tyrosine phosphorylation / cell maturation / 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 / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / cellular response to reactive oxygen species / non-membrane spanning protein tyrosine kinase activity / apoptotic signaling pathway / calcium-mediated signaling / 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 / 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 / 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: 1.73 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
DepositionOct 20, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2026Provider: repository / Type: Initial release
Revision 1.1Jun 3, 2026Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)82,37418
Polymers79,8684
Non-polymers2,50714
Water4,774265
1
A: Tyrosine-protein kinase BTK
C: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,55010
Polymers39,9342
Non-polymers1,6168
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2790 Å2
ΔGint-27 kcal/mol
Surface area17200 Å2
MethodPISA
2
G: Tyrosine-protein kinase BTK
J: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8258
Polymers39,9342
Non-polymers8916
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2510 Å2
ΔGint-26 kcal/mol
Surface area17250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.988, 66.656, 79.860
Angle α, β, γ (deg.)90.00, 98.68, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ACGJ

#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
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, 279 molecules

#2: Chemical ChemComp-A1JS1 / (6~{R})-6-(2-bromanyl-6-chloranyl-phenyl)-4-oxidanylidene-6,7-dihydro-5~{H}-1-benzofuran-3-carboxylic acid


Mass: 369.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H10BrClO4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-A1JS0 / (6~{R})-6-(2-bromanyl-6-chloranyl-phenyl)-4,5,6,7-tetrahydro-1-benzofuran-3-carboxylic acid


Mass: 355.611 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C15H12BrClO3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-MG / MAGNESIUM ION


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


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 265 / 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: 2.3 Å3/Da / Density % sol: 46.45 %
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: 0.9184 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Feb 15, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.73→50.93 Å / Num. obs: 74878 / % possible obs: 100 % / Redundancy: 7 % / Biso Wilson estimate: 38.99 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.08 / Rpim(I) all: 0.033 / Rrim(I) all: 0.087 / Net I/σ(I): 13.2 / Num. measured all: 523123
Reflection shellResolution: 1.73→1.76 Å / % possible obs: 99.7 % / Redundancy: 7.1 % / Rmerge(I) obs: 4.947 / Num. measured all: 26377 / Num. unique obs: 3698 / CC1/2: 0.323 / Rpim(I) all: 1.994 / Rrim(I) all: 5.339 / Net I/σ(I) obs: 0.2

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (10-JUL-2024)refinement
DIALSdata scaling
XDSdata reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.73→24.66 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.914 / SU R Cruickshank DPI: 0.155 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.152 / SU Rfree Blow DPI: 0.151 / SU Rfree Cruickshank DPI: 0.153
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=MG ZN. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=6064. NUMBER ...Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=MG ZN. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=6064. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=8. NUMBER TREATED BY BAD NON-BONDED CONTACTS=2.
RfactorNum. reflection% reflectionSelection details
Rfree0.3015 1970 2.76 %RANDOM
Rwork0.2478 ---
obs0.2492 71430 95.5 %-
Displacement parametersBiso mean: 55.26 Å2
Baniso -1Baniso -2Baniso -3
1--8.3254 Å20 Å2-4.0841 Å2
2---5.4494 Å20 Å2
3---13.7749 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 1.73→24.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5561 0 128 292 5981
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0095934HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.038085HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2188SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1014HARMONIC5
X-RAY DIFFRACTIONt_it5880HARMONIC10
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.58
X-RAY DIFFRACTIONt_other_torsion18.97
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion719SEMIHARMONIC5
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_contact4781SEMIHARMONIC4
LS refinement shellResolution: 1.73→1.76 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.56 -2.38 %
Rwork0.5126 1395 -
all0.5137 1429 -
obs--34.59 %

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