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- PDB-8fd9: Structure of BTK kinase domain with the second-generation inhibit... -

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Basic information

Entry
Database: PDB / ID: 8fd9
TitleStructure of BTK kinase domain with the second-generation inhibitor acalabrutinib
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / inhibitor / kinase / complex / covalent / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of B cell activation / G beta:gamma signalling through BTK / RHO GTPases Activate WASPs and WAVEs / FCERI mediated Ca+2 mobilization / G alpha (q) signalling events / G alpha (12/13) signalling events / negative regulation of leukocyte proliferation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of actin dynamics for phagocytic cup formation / proteoglycan catabolic process ...negative regulation of B cell activation / G beta:gamma signalling through BTK / RHO GTPases Activate WASPs and WAVEs / FCERI mediated Ca+2 mobilization / G alpha (q) signalling events / G alpha (12/13) signalling events / negative regulation of leukocyte proliferation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of actin dynamics for phagocytic cup formation / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / 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 / DAP12 signaling / negative regulation of cytokine production / positive regulation of immunoglobulin production / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / positive regulation of phagocytosis / positive regulation of B cell proliferation / cell maturation / non-specific protein-tyrosine kinase / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / positive regulation of interleukin-6 production / cellular response to reactive oxygen species / positive regulation of tumor necrosis factor production / T cell receptor signaling pathway / cytoplasmic vesicle / protein tyrosine kinase activity / response to lipopolysaccharide / adaptive immune response / intracellular signal transduction / membrane raft / innate immune response / apoptotic process / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / metal ion binding / 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
BROMIDE ION / Chem-XQQ / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsLin, D.Y. / Andreotti, A.H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Plos One / Year: 2023
Title: Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib.
Authors: Lin, D.Y. / Andreotti, A.H.
History
DepositionDec 2, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 2.0Aug 23, 2023Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly / pdbx_validate_close_contact / struct_conn
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 2.1Sep 13, 2023Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6096
Polymers31,8221
Non-polymers7875
Water4,810267
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)42.921, 50.310, 123.483
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 31821.521 Da / Num. of mol.: 1
Mutation: K430R, L542M S543T, V555T, R562K, S564A, P565S, Y617P
Source method: isolated from a genetically manipulated source
Details: Bruton's Tyrosine Kinase in complex with acalabrutinib
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Btk, Bpk / Production host: Escherichia coli (E. coli)
References: UniProt: P35991, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-XQQ / 4-[(4S)-8-amino-3-{(2S)-1-[(2E)-but-2-enoyl]pyrrolidin-2-yl}imidazo[1,5-a]pyrazin-1-yl]-N-(pyridin-2-yl)benzamide / 4-{(4S)-8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide


Mass: 467.522 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: Br
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 267 / 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: 2.25 Å3/Da / Density % sol: 45.37 %
Crystal growTemperature: 277 K / Method: evaporation / pH: 6.5
Details: 20% PEG 3350, 0.1M Bis-tris propane, pH 6.5 and 0.2M sodium bromide
PH range: 6.5-7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Jul 7, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.626→46.591 Å / Num. obs: 28343 / % possible obs: 82.2 % / Redundancy: 5.5 % / Biso Wilson estimate: 17.65 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.148 / Rpim(I) all: 0.064 / Rrim(I) all: 0.162 / Net I/σ(I): 1.2
Reflection shellResolution: 1.626→1.745 Å / Redundancy: 5.4 % / Rmerge(I) obs: 1.276 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1418 / CC1/2: 0.499 / Rpim(I) all: 0.582 / % possible all: 21.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROCdata processing
PHASERphasing
autoPROCdata reduction
XDSdata scaling
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→19.74 Å / SU ML: 0.2131 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.8202
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2276 1394 5 %
Rwork0.1866 26477 -
obs0.1887 27871 92.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.15 Å2
Refinement stepCycle: LAST / Resolution: 1.7→19.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2215 0 39 267 2521
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00162339
X-RAY DIFFRACTIONf_angle_d0.47453159
X-RAY DIFFRACTIONf_chiral_restr0.0388328
X-RAY DIFFRACTIONf_plane_restr0.0032402
X-RAY DIFFRACTIONf_dihedral_angle_d12.0686905
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.760.3058680.26831394X-RAY DIFFRACTION49.29
1.76-1.830.34721200.26192428X-RAY DIFFRACTION86.08
1.83-1.910.29951550.25312744X-RAY DIFFRACTION97.64
1.91-2.020.26681360.22752851X-RAY DIFFRACTION99.3
2.02-2.140.22991550.20512806X-RAY DIFFRACTION99.16
2.14-2.310.24181510.19642779X-RAY DIFFRACTION98.32
2.31-2.540.24871510.18022833X-RAY DIFFRACTION98.09
2.54-2.90.22681380.182817X-RAY DIFFRACTION98.04
2.91-3.660.20081520.15842861X-RAY DIFFRACTION98.08
3.66-19.740.19071680.16442964X-RAY DIFFRACTION97.48
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.8218960953-0.488182390054-0.7041913855515.20963977625-0.06546822105844.74547855641-0.00589924448315-0.01813020282360.09687358313050.04047873761710.0530893188690.184941566486-0.221711185191-0.00757984045861-0.05057476350380.0825913905782-0.0188744107824-0.02576737344840.11228395385-0.0009837894401610.10669470111420.13385686638.53865657814-4.29057465894
28.450881974680.66075481929-2.053295120248.78485268423-2.972204954853.35022202554-0.241043617165-0.08128362098290.2787757092160.6428190147080.134620420848-0.260575134961-0.159141759781-0.2633889307140.08974799299340.327602170707-0.0952718119948-0.03801662616580.273629985637-0.007781979402820.12977579958119.57862972319.24648990128-20.4533917583
37.122417730356.793068501241.665109015568.562160416392.177518252291.06864507080.0122858055346-0.2025418775760.3237669301390.0227267193544-0.1960973534920.464437125278-0.0565893232666-0.08696633302280.1561573898950.1440130294770.03446937245850.002963452351060.09754135737640.01978146060840.11890359617614.25224570477.99377316735-11.8047370851
41.785710460821.69346312440.09275335887972.59607374273-0.2487105127520.865905480320.122710515056-0.104467267997-0.08174587345650.26545464597-0.1069047752980.06969631097390.10164014627-0.0903911935485-0.00263001413750.1246131474950.01756376897270.03267338547910.1093166620350.01764653551940.1533027904239.03217632022-7.4164328122-9.04356805148
58.45964927291-0.714346680374-5.182412372591.17956082720.4322090765425.30795326254-0.0783076974410.137230829180.3094945886680.005737384896110.04097544848720.00424452345616-0.0206491745810.0913902986050.01721924407190.129461512828-0.00918190679205-0.02176587996520.08898187002010.002704517701940.14503906954922.2355497744-2.47971232678-18.2191200112
61.90979441892-0.0965548495061-0.6029392192092.24369386952-0.9051054085472.41219710055-0.01892459770390.102296552365-0.113120181585-0.138603684782-0.02995368110940.03543415501540.1589833732090.009390005363310.04658793480290.09963393988320.001818024758790.002587373167110.087025573983-0.02488415027960.096043018927615.4691055458-19.7137826638-20.0167899623
76.061369319817.22892198487-4.962250229358.83982903001-5.690719928934.29220083618-0.01306543500360.2560576915910.01784783652370.07193415261640.2900339369360.1333001656720.060597588481-0.305483431009-0.2878809448420.12821988048-0.00940065221237-0.026706238140.2254832501720.04391594366110.213316022101-5.93341287652-20.2001623661-15.6847316375
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 395 through 438 )395 - 4381 - 44
22chain 'A' and (resid 439 through 451 )439 - 45145 - 57
33chain 'A' and (resid 452 through 470 )452 - 47058 - 76
44chain 'A' and (resid 471 through 534 )471 - 53477 - 140
55chain 'A' and (resid 535 through 552 )535 - 552141 - 158
66chain 'A' and (resid 553 through 643 )553 - 643159 - 249
77chain 'A' and (resid 644 through 665 )644 - 665250 - 271

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