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- PDB-7l5p: Crystal structure of the covalently bonded complex of rilzabrutin... -

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Basic information

Entry
Database: PDB / ID: 7l5p
TitleCrystal structure of the covalently bonded complex of rilzabrutinib with BTK
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PROTEIN KINASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX / TRANSFERASE
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
Chem-R1L / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.14 Å
AuthorsBradshaw, J.M. / Brameld, K.A. / Mrosek, M. / Lammens, A. / Blaesse, M.
CitationJournal: To Be Published
Title: The Discovery Rilzabrutinib (PRN1008): A Reversible Covalent BTK Inhibitor for Immune Mediated Diseases
Authors: Owens, T.D.
History
DepositionDec 22, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 29, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9409
Polymers63,1972
Non-polymers1,7447
Water3,963220
1
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4564
Polymers31,5981
Non-polymers8583
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4845
Polymers31,5981
Non-polymers8864
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.810, 76.684, 88.321
Angle α, β, γ (deg.)90.000, 96.460, 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: 31598.287 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-R1L / (2E)-2-{(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl}-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile / Rilzabrutinib


Mass: 665.760 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H40FN9O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 220 / Source method: isolated from a natural source / Formula: H2O
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: 2.44 Å3/Da / Density % sol: 49.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: PEG 5000 MME AMMONIUM SULFATE MES / PH range: 6-7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jun 17, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 2.14→87.76 Å / Num. obs: 30980 / % possible obs: 96.3 % / Redundancy: 2.89 % / Biso Wilson estimate: 31.658 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.096 / Rrim(I) all: 0.116 / Χ2: 0.947 / Net I/σ(I): 9.43
Reflection shellResolution: 2.14→2.39 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.437 / Mean I/σ(I) obs: 2.71 / Num. unique obs: 8805 / CC1/2: 0.81 / Rrim(I) all: 0.529 / % possible all: 97.6

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PREVIOUSLY SOLVED STRUCTURE

Resolution: 2.14→87.76 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.905 / SU B: 7.129 / SU ML: 0.182 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.323 / ESU R Free: 0.226 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2582 1569 5.1 %RANDOM
Rwork0.2237 ---
obs0.2255 29411 96.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 74.11 Å2 / Biso mean: 27.536 Å2 / Biso min: 3.19 Å2
Baniso -1Baniso -2Baniso -3
1--0.45 Å2-0 Å2-0.43 Å2
2--1.31 Å20 Å2
3----0.74 Å2
Refinement stepCycle: final / Resolution: 2.14→87.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4378 0 121 223 4722
Biso mean--23.31 30.72 -
Num. residues----534
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0194540
X-RAY DIFFRACTIONr_bond_other_d0.0010.024202
X-RAY DIFFRACTIONr_angle_refined_deg1.4581.9846161
X-RAY DIFFRACTIONr_angle_other_deg2.62539643
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3545546
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.77723.673196
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.5715765
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5081525
X-RAY DIFFRACTIONr_chiral_restr0.0730.2660
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025048
X-RAY DIFFRACTIONr_gen_planes_other0.0080.021061
LS refinement shellResolution: 2.14→2.196 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 130 -
Rwork0.294 2204 -
all-2334 -
obs--97.62 %

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