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- PDB-8gc7: Bruton's tyrosine kinase in complex with 5-(piperidin-1-yl)-3-{[4... -

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Basic information

Entry
Database: PDB / ID: 8gc7
TitleBruton's tyrosine kinase in complex with 5-(piperidin-1-yl)-3-{[4-(piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide
ComponentsTyrosine-protein kinase BTK
KeywordsSIGNALING PROTEIN / degrader / 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-YXJ / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsGajewski, S.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Science / Year: 2024
Title: Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
Authors: Montoya, S. / Bourcier, J. / Noviski, M. / Lu, H. / Thompson, M.C. / Chirino, A. / Jahn, J. / Sondhi, A.K. / Gajewski, S. / Tan, Y.S.M. / Yung, S. / Urban, A. / Wang, E. / Han, C. / Mi, X. / ...Authors: Montoya, S. / Bourcier, J. / Noviski, M. / Lu, H. / Thompson, M.C. / Chirino, A. / Jahn, J. / Sondhi, A.K. / Gajewski, S. / Tan, Y.S.M. / Yung, S. / Urban, A. / Wang, E. / Han, C. / Mi, X. / Kim, W.J. / Sievers, Q. / Auger, P. / Bousquet, H. / Brathaban, N. / Bravo, B. / Gessner, M. / Guiducci, C. / Iuliano, J.N. / Kane, T. / Mukerji, R. / Reddy, P.J. / Powers, J. / Sanchez Garcia de Los Rios, M. / Ye, J. / Barrientos Risso, C. / Tsai, D. / Pardo, G. / Notti, R.Q. / Pardo, A. / Affer, M. / Nawaratne, V. / Totiger, T.M. / Pena-Velasquez, C. / Rhodes, J.M. / Zelenetz, A.D. / Alencar, A. / Roeker, L.E. / Mehta, S. / Garippa, R. / Linley, A. / Soni, R.K. / Skanland, S.S. / Brown, R.J. / Mato, A.R. / Hansen, G.M. / Abdel-Wahab, O. / Taylor, J.
History
DepositionMar 1, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 31, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 14, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 21, 2024Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)32,0515
Polymers31,5111
Non-polymers5404
Water4,486249
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.993, 76.032, 105.120
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


Mass: 31511.209 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-YXJ / 5-(piperidin-1-yl)-3-[4-(piperidin-4-yl)anilino]pyrazine-2-carboxamide


Mass: 380.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / 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: 2.41 Å3/Da / Density % sol: 48.94 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.06 M Magnesium chloride hexahydrate, 0.06 M Calcium chloride dihydrate, 0.1M Imidazole, 0.1M MES monohydrate, 24% v/v PEG 500 MME, 12 % w/v PEG 20000, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.977 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Nov 4, 2022
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 1.9→61.61 Å / Num. obs: 24811 / % possible obs: 100 % / Redundancy: 6.3 % / Biso Wilson estimate: 12.48 Å2 / CC1/2: 0.973 / Net I/σ(I): 4.8
Reflection shellResolution: 1.9→1.95 Å / Redundancy: 5.8 % / Num. unique obs: 1700 / CC1/2: 0.428 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→61.61 Å / SU ML: 0.1953 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 20.557
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2269 2000 8.08 %random
Rwork0.192 22751 --
obs0.1948 24751 99.98 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 12.92 Å2
Refinement stepCycle: LAST / Resolution: 1.9→61.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2170 0 37 249 2456
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00332292
X-RAY DIFFRACTIONf_angle_d0.68643102
X-RAY DIFFRACTIONf_chiral_restr0.0444326
X-RAY DIFFRACTIONf_plane_restr0.0064393
X-RAY DIFFRACTIONf_dihedral_angle_d6.486338
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.950.29861380.2611562X-RAY DIFFRACTION99.94
1.95-20.28251430.24521626X-RAY DIFFRACTION100
2-2.060.27221380.23391586X-RAY DIFFRACTION100
2.06-2.130.26331420.22261608X-RAY DIFFRACTION100
2.13-2.20.24491390.20971589X-RAY DIFFRACTION100
2.2-2.290.24661410.21221601X-RAY DIFFRACTION99.94
2.29-2.390.2741420.20461608X-RAY DIFFRACTION100
2.39-2.520.2431410.20391604X-RAY DIFFRACTION100
2.52-2.680.25081430.20991627X-RAY DIFFRACTION100
2.68-2.880.27731430.20741622X-RAY DIFFRACTION99.94
2.88-3.170.23911450.19161649X-RAY DIFFRACTION100
3.18-3.630.20411430.16981633X-RAY DIFFRACTION100
3.64-4.580.14111460.13421660X-RAY DIFFRACTION100
4.58-61.610.17561560.16131776X-RAY DIFFRACTION99.95
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)
13.40354558763-0.21821996253-0.2819984945160.8377188664221.046955014692.28861985747-0.213959388695-0.218333117850.209822293843-0.180707458770.117534845593-0.0988777505572-0.241224951816-0.03133241310340.07540177920380.1520244910170.03646079972250.01136801550070.120562810593-0.04973061336180.1342715286623.450122971230.408088887429-0.587786679268
20.974322027196-0.1167768604660.4195914942671.41281022363-0.2361944559190.3871793554340.0145158498821-0.1126375893790.06241700372510.0631743124685-0.009124501505660.04300534462770.0108541104244-0.00168899229295-0.004053234504410.07563783060350.007120133851280.004960346481590.0893611902956-0.01526786880350.03398059670180.531469151214-4.57486326146-7.71908214465
31.39075450167-0.153472849945-0.3216482385720.3935207591530.2248756265310.399004488356-0.01970937277580.0113734634396-0.0353631840304-0.04089390097470.0420884506955-0.08712983576010.01991259763170.0445062596104-0.03166484918750.0516749696116-0.00247898752621-0.02185541380370.07655892874750.0006339046230010.041285391618213.2213822515-17.3854108047-13.9724069046
41.49423039090.0608258885529-0.1648763742781.048584836750.3037842801950.1674347685920.0395707889047-0.169745536811-0.02858698851450.02340217146030.01409938710230.0651842876374-0.00871645955617-0.0470676701179-0.03847830844090.05643373018240.0007124254249930.0003960803220110.08122377876830.006692948097940.036090866791.24644168751-14.1158857249-15.9273593732
52.947728241051.21735033794-1.047110419692.6573855306-0.4453624302461.63738209239-0.1189628604770.168551666490.0300980317791-0.1130400141490.1024881822910.141917816062-0.045583561591-0.202748033145-0.005692115350110.05385699855670.00919579330014-0.01802652157860.0807491355239-0.006997915624790.0544028793808-5.09507476726-20.2501951892-28.2886385428
61.419319425720.009326659501690.6107828884681.09523422039-0.2029718425061.09634442392-0.03592595139410.2259886732680.0735370192285-0.0529060104471-0.00896828310657-0.0147710415221-0.03090301236460.05557690104360.03575215256790.0420158510687-0.00923651091259-0.0121828341620.0719136320963-0.002859217404950.05000455719367.29719129806-24.256038362-29.6220901484
71.74724811524-0.2714306841830.8467730963471.90280825387-0.065343688743.44349653815-0.0874908370009-0.0280311736517-0.08295634762450.0599707793535-0.00383560965159-0.05581067315770.01692064611040.02659611443590.0514973017870.0623603872982-0.00802728255320.007128914950330.0315721658451-0.01086994772450.06226375643397.94658523673-33.9430689749-19.1721033625
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 389 through 407 )389 - 4071 - 19
22chain 'A' and (resid 408 through 470 )408 - 47020 - 82
33chain 'A' and (resid 471 through 514 )471 - 51483 - 126
44chain 'A' and (resid 515 through 552 )515 - 552127 - 164
55chain 'A' and (resid 553 through 575 )553 - 575165 - 187
66chain 'A' and (resid 576 through 623 )576 - 623188 - 235
77chain 'A' and (resid 624 through 658 )624 - 658236 - 270

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