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- PDB-6xe4: BTK Fluorocyclopropyl amide inhibitor, Compound 25 -

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Basic information

Entry
Database: PDB / ID: 6xe4
TitleBTK Fluorocyclopropyl amide inhibitor, Compound 25
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / kinase / inhibitor / inflammation / drug / TRANSFERASE / 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
Chem-V1G / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsKiefer, J.R. / Crawford, J.J. / Lee, W. / Eigenbrot, C. / Yu, C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Stereochemical Differences in Fluorocyclopropyl Amides Enable Tuning of Btk Inhibition and Off-Target Activity.
Authors: Crawford, J.J. / Lee, W. / Johnson, A.R. / Delatorre, K.J. / Chen, J. / Eigenbrot, C. / Heidmann, J. / Kakiuchi-Kiyota, S. / Katewa, A. / Kiefer, J.R. / Liu, L. / Lubach, J.W. / Misner, D. / ...Authors: Crawford, J.J. / Lee, W. / Johnson, A.R. / Delatorre, K.J. / Chen, J. / Eigenbrot, C. / Heidmann, J. / Kakiuchi-Kiyota, S. / Katewa, A. / Kiefer, J.R. / Liu, L. / Lubach, J.W. / Misner, D. / Purkey, H. / Reif, K. / Vogt, J. / Wong, H. / Yu, C. / Young, W.B.
History
DepositionJun 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5584
Polymers33,8311
Non-polymers7283
Water4,846269
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)108.280, 108.280, 42.202
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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Components

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


Mass: 33830.727 Da / Num. of mol.: 1
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-V1G / (1S,2S)-N-[2'-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-3'-(hydroxymethyl)-1-methyl-6-oxo[1,6-dihydro[3,4'-bipyridine]]-5-yl]-2-fluorocyclopropane-1-carboxamide


Mass: 535.542 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H27F2N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 269 / 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: 2.11 Å3/Da / Density % sol: 41.74 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 7 / Details: PEG 10000, Li2SO4, pH 7.0

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX225-HS / Detector: CCD / Date: Apr 9, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.6→35 Å / Num. obs: 37127 / % possible obs: 98.8 % / Redundancy: 7.6 % / Biso Wilson estimate: 17.62 Å2 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.032 / Rrim(I) all: 0.091 / Χ2: 0.932 / Net I/σ(I): 7.7 / Num. measured all: 281402
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.6-1.6360.80217580.5410.3460.8760.51593.9
1.63-1.666.70.79418510.6850.3260.8590.49899.5
1.66-1.696.90.66517970.7870.2690.7190.50196.1
1.69-1.726.90.56918490.8410.2290.6140.52699.9
1.72-1.767.10.49118260.8690.1970.5290.5596.6
1.76-1.87.10.41618270.910.1650.4480.566100
1.8-1.857.40.33818350.9460.1320.3630.57697.2
1.85-1.97.40.29118570.9630.1130.3120.60699.7
1.9-1.957.70.24518240.9730.0940.2630.66698.2
1.95-2.027.80.18718620.9820.0710.20.67698.5
2.02-2.097.90.1618630.9890.060.1720.75199.9
2.09-2.1780.12518430.9920.0470.1330.75598.8
2.17-2.278.10.11418510.9940.0420.1220.82199.1
2.27-2.398.10.09618730.9960.0360.1020.84699.3
2.39-2.548.10.08418780.9970.0310.090.95699.5
2.54-2.748.10.07918710.9960.0290.0851.17299.7
2.74-3.018.10.07718940.9960.0290.0821.67599.7
3.01-3.458.10.06818940.9970.0250.0722.08799.8
3.45-4.348.10.04819090.9990.0180.0511.74699.8
4.34-357.80.04119650.9980.0160.0431.4999.8

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHENIX1.16-3549-000refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Null

Resolution: 1.6→33.284 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 16.76 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1804 1912 5.15 %
Rwork0.1577 35205 -
obs0.1589 37117 98.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 89.4 Å2 / Biso mean: 26.5849 Å2 / Biso min: 9.32 Å2
Refinement stepCycle: final / Resolution: 1.6→33.284 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2133 0 51 276 2460
Biso mean--22.12 35.79 -
Num. residues----264
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052281
X-RAY DIFFRACTIONf_angle_d0.7923100
X-RAY DIFFRACTIONf_chiral_restr0.047326
X-RAY DIFFRACTIONf_plane_restr0.004395
X-RAY DIFFRACTIONf_dihedral_angle_d18.0691344
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.6-1.63980.24121260.2444243296
1.6398-1.68410.2721550.2226245297
1.6841-1.73360.20931330.2008247399
1.7336-1.78960.22161420.1835249198
1.7896-1.85360.20841280.1772247898
1.8536-1.92780.23811400.167248799
1.9278-2.01550.19761540.1578249799
2.0155-2.12170.18671240.1469252299
2.1217-2.25460.18651320.1459253199
2.2546-2.42870.17271320.14562526100
2.4287-2.6730.16841300.15122549100
2.673-3.05950.18031450.15752552100
3.0595-3.85380.17311430.14642570100
3.8538-33.20.14021280.15042645100
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)
10.15040.11140.1050.4249-0.02390.318-0.09410.0043-0.23260.04190.02340.08420.12610.0769-00.17130.01730.02560.13740.02920.2291-35.564-39.26367.3702
21.8773-0.31260.6760.2626-0.290.48870.37070.3655-0.5384-0.3331-0.13040.20440.40580.12850.01740.26230.0584-0.07330.1726-0.06190.2968-38.2027-37.0593-3.9529
31.1753-0.2156-0.46820.7597-0.64031.3284-0.0435-0.0277-0.0586-0.02190.02760.0841-0.08080.0907-0.00130.11120.0108-0.02440.10580.02070.1158-32.5988-26.64434.5211
40.4392-0.03210.06020.2982-0.14480.1864-0.06730.13650.0481-0.03650.0814-0.1553-0.04160.40660.00220.1597-0.0132-0.01220.17860.01580.1159-24.3832-17.5838-4.1492
50.41810.1416-0.07020.54120.01390.6815-0.03460.1909-0.1073-0.1077-0.0038-0.01490.05910.2566-0.00580.12770.0192-0.00410.10330.01170.0983-32.392-22.3943-1.7602
60.8423-0.1994-0.36030.3846-0.09280.22710.0730.4377-0.1827-0.13460.00950.27090.1022-0.0011-0.00530.15630.0022-0.06670.13760.00430.1906-41.4068-26.7633-6.0189
72.2392-0.5856-0.9141.26570.14360.5287-0.17850.8388-0.4358-0.1778-0.14390.3281-0.0531-0.3229-0.81050.1685-0.0338-0.0607-0.00920.1587-0.0389-40.1892-14.24-9.863
80.423-0.0449-0.35690.03240.24892.0811-0.20440.05620.24450.0886-0.03360.1838-0.438-0.29680.02020.2223-0.0052-0.0340.12880.00330.1882-46.0396-6.5287-3.2352
90.8316-0.18280.21330.4416-0.0071.0337-0.26760.32730.7128-0.20330.05910.0345-0.58080.1933-1.03760.269-0.0727-0.09490.11990.13150.1557-32.8121-3.9202-9.32
101.1894-1.529-0.58921.98970.76940.9972-0.0623-0.10570.33340.21920.0717-0.5185-0.18340.59460.12780.2119-0.09-0.03320.30180.06270.1977-19.2277-9.4119-6.6074
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 395 through 424 )A395 - 424
2X-RAY DIFFRACTION2chain 'A' and (resid 425 through 451 )A425 - 451
3X-RAY DIFFRACTION3chain 'A' and (resid 452 through 494 )A452 - 494
4X-RAY DIFFRACTION4chain 'A' and (resid 495 through 515 )A495 - 515
5X-RAY DIFFRACTION5chain 'A' and (resid 516 through 534 )A516 - 534
6X-RAY DIFFRACTION6chain 'A' and (resid 535 through 552 )A535 - 552
7X-RAY DIFFRACTION7chain 'A' and (resid 553 through 591 )A553 - 591
8X-RAY DIFFRACTION8chain 'A' and (resid 592 through 611 )A592 - 611
9X-RAY DIFFRACTION9chain 'A' and (resid 612 through 643 )A612 - 643
10X-RAY DIFFRACTION10chain 'A' and (resid 644 through 658 )A644 - 658

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