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- PDB-8fll: Crystal structure of BTK kinase domain in complex with pirtobrutinib -

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Basic information

Entry
Database: PDB / ID: 8fll
TitleCrystal structure of BTK kinase domain in complex with pirtobrutinib
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/INHIBITOR / BTK inhibitor / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic 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 / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / cellular response to interleukin-7 / MyD88 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / positive regulation of immunoglobulin production / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / B cell activation / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / RHO GTPases Activate WASPs and WAVEs / positive regulation of B cell proliferation / positive regulation of phagocytosis / cell maturation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calcium-mediated signaling / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / cellular response to reactive oxygen species / peptidyl-tyrosine phosphorylation / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / G alpha (12/13) signalling events / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / G alpha (q) signalling events / protein tyrosine kinase activity / adaptive immune response / Potential therapeutics for SARS / response to lipopolysaccharide / intracellular signal transduction / membrane raft / protein phosphorylation / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / metal ion binding / 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 / SH3 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
pirtobrutinib / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.498 Å
AuthorsCedervall, E.P. / Morales, T.H. / Allerston, C.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Blood / Year: 2023
Title: Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor.
Authors: Gomez, E.B. / Ebata, K. / Randeria, H.S. / Rosendahl, M.S. / Cedervall, E.P. / Morales, T.H. / Hanson, L.M. / Brown, N.E. / Gong, X. / Stephens, J. / Wu, W. / Lippincott, I. / Ku, K.S. / ...Authors: Gomez, E.B. / Ebata, K. / Randeria, H.S. / Rosendahl, M.S. / Cedervall, E.P. / Morales, T.H. / Hanson, L.M. / Brown, N.E. / Gong, X. / Stephens, J. / Wu, W. / Lippincott, I. / Ku, K.S. / Walgren, R.A. / Abada, P.B. / Ballard, J.A. / Allerston, C.K. / Brandhuber, B.J.
History
DepositionDec 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 1, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2023Group: Refinement description / Structure summary
Category: audit_author / pdbx_initial_refinement_model ...audit_author / pdbx_initial_refinement_model / refine / software
Item: _pdbx_initial_refinement_model.details / _pdbx_initial_refinement_model.source_name ..._pdbx_initial_refinement_model.details / _pdbx_initial_refinement_model.source_name / _refine.pdbx_starting_model / _software.version
Revision 1.2Mar 15, 2023Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Jul 12, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.4May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7556
Polymers31,7871
Non-polymers9695
Water3,027168
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.482, 67.269, 90.383
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 31786.537 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q06187, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 173 molecules

#2: Chemical ChemComp-Y7W / pirtobrutinib / 5-amino-3-{4-[(5-fluoro-2-methoxybenzamido)methyl]phenyl}-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carboxamide


Mass: 479.427 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21F4N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 1.98 Å3/Da / Density % sol: 37.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 31% PEG3350, 0.3 M ammonium sulfate, 0.1 M Bis-Tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 28, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.498→53.963 Å / Num. obs: 40714 / % possible obs: 98.2 % / Redundancy: 5.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.024 / Rrim(I) all: 0.055 / Net I/σ(I): 16
Reflection shellResolution: 1.498→1.524 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.835 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2035 / CC1/2: 0.838 / Rpim(I) all: 0.424 / Rrim(I) all: 0.94 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
autoPROCv1.1.7data reduction
autoPROCv1.1.7data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: A proprietary model of same protein with another ligand

Resolution: 1.498→21.76 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.955 / SU R Cruickshank DPI: 0.077 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.08 / SU Rfree Blow DPI: 0.075 / SU Rfree Cruickshank DPI: 0.073
RfactorNum. reflection% reflectionSelection details
Rfree0.2019 1957 -RANDOM
Rwork0.185 ---
obs0.1858 40700 98.2 %-
Displacement parametersBiso mean: 27.54 Å2
Baniso -1Baniso -2Baniso -3
1--1.6616 Å20 Å20 Å2
2---0.9464 Å20 Å2
3---2.608 Å2
Refine analyzeLuzzati coordinate error obs: 0.18 Å
Refinement stepCycle: LAST / Resolution: 1.498→21.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2069 0 65 168 2302
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0112290HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.093123HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d796SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes402HARMONIC5
X-RAY DIFFRACTIONt_it2290HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion290SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies14HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact2259SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.02
X-RAY DIFFRACTIONt_other_torsion14.57
LS refinement shellResolution: 1.5→1.51 Å
RfactorNum. reflection% reflection
Rfree0.2734 46 -
Rwork0.2455 --
obs0.2471 814 99.62 %
Refinement TLS params.Origin x: -20.686 Å / Origin y: 5.9956 Å / Origin z: -10.7168 Å
111213212223313233
T0.0035 Å20.0025 Å20.0141 Å2--0.0229 Å2-0.0077 Å2---0.0198 Å2
L0.4581 °2-0.0196 °2-0.1991 °2-0.4463 °2-0.4503 °2--0.6491 °2
S-0.0173 Å °0.0123 Å °0.0026 Å °0.0123 Å °-0.0397 Å °0.0272 Å °0.0026 Å °0.0272 Å °0.057 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A395 - 658
2X-RAY DIFFRACTION1{ A|* }A701 - 705

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