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- PDB-8u2d: Bruton's tyrosine kinase in complex with N-[(2R)-1-[(3R)-3-(methy... -

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Basic information

Entry
Database: PDB / ID: 8u2d
TitleBruton's tyrosine kinase in complex with N-[(2R)-1-[(3R)-3-(methylcarbamoyl)-1H,2H,3H,4H,9H-pyrido[3,4-b]indol-2-yl]-3-(3-methylphenyl)-1-oxopropan-2-yl]-1H-indazole-5-carboxamide
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / protein degradation / leukemia
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 / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of immunoglobulin production / positive regulation of B cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / mesoderm development / Fc-epsilon receptor signaling pathway / B cell activation / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / RHO GTPases Activate WASPs and WAVEs / positive regulation of phagocytosis / positive regulation of B cell proliferation / cell maturation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / apoptotic signaling pathway / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / calcium-mediated signaling / Regulation of actin dynamics for phagocytic cup formation / peptidyl-tyrosine phosphorylation / G beta:gamma signalling through BTK / positive regulation of interleukin-6 production / cellular response to reactive oxygen species / 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 / protein tyrosine kinase activity / G alpha (q) signalling events / adaptive immune response / response to lipopolysaccharide / Potential therapeutics for SARS / intracellular signal transduction / protein phosphorylation / membrane raft / innate immune response / 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
Chem-UQX / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsGajewski, S. / Clifton, M.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.
Authors: Robbins, D.W. / Noviski, M.A. / Tan, Y.S. / Konst, Z.A. / Kelly, A. / Auger, P. / Brathaban, N. / Cass, R. / Chan, M.L. / Cherala, G. / Clifton, M.C. / Gajewski, S. / Ingallinera, T.G. / ...Authors: Robbins, D.W. / Noviski, M.A. / Tan, Y.S. / Konst, Z.A. / Kelly, A. / Auger, P. / Brathaban, N. / Cass, R. / Chan, M.L. / Cherala, G. / Clifton, M.C. / Gajewski, S. / Ingallinera, T.G. / Karr, D. / Kato, D. / Ma, J. / McKinnell, J. / McIntosh, J. / Mihalic, J. / Murphy, B. / Panga, J.R. / Peng, G. / Powers, J. / Perez, L. / Rountree, R. / Tenn-McClellan, A. / Sands, A.T. / Weiss, D.R. / Wu, J. / Ye, J. / Guiducci, C. / Hansen, G. / Cohen, F.
History
DepositionSep 5, 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.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _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)32,3587
Polymers31,5111
Non-polymers8476
Water2,900161
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.390, 79.340, 106.880
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

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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: 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

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Non-polymers , 6 types, 167 molecules

#2: Chemical ChemComp-UQX / (3R)-2-[N-(1H-indazole-5-carbonyl)-3-methyl-D-phenylalanyl]-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide


Mass: 534.608 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H30N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 161 / 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: 2.58 Å3/Da / Density % sol: 52.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 30% EDO_P8K, 0.03M NaF, 0.03M, NaBr, 0.03M NaI, 0.05M Sodium HEPES, 0.05M MOPS pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→44.32 Å / Num. obs: 24245 / % possible obs: 98.57 % / Redundancy: 6.6 % / Biso Wilson estimate: 25.53 Å2 / CC1/2: 0.992 / CC star: 0.998 / Rmerge(I) obs: 0.2275 / Rpim(I) all: 0.0955 / Rrim(I) all: 0.2471 / Net I/σ(I): 7.76
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 6.9 % / Rmerge(I) obs: 1.922 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 2338 / CC1/2: 0.374 / CC star: 0.738 / Rpim(I) all: 0.7859 / Rrim(I) all: 2.079 / % possible all: 96.93

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→44.32 Å / SU ML: 0.2791 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.4986
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2384 1196 4.94 %
Rwork0.1905 23035 -
obs0.1928 24231 98.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.43 Å2
Refinement stepCycle: LAST / Resolution: 1.95→44.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2176 0 56 161 2393
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00752313
X-RAY DIFFRACTIONf_angle_d0.87313136
X-RAY DIFFRACTIONf_chiral_restr0.0525328
X-RAY DIFFRACTIONf_plane_restr0.0072400
X-RAY DIFFRACTIONf_dihedral_angle_d5.7021345
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-2.030.37051170.312489X-RAY DIFFRACTION97.13
2.03-2.120.31221330.26912516X-RAY DIFFRACTION98.7
2.12-2.230.32391190.24852531X-RAY DIFFRACTION98.73
2.23-2.370.30871270.23362512X-RAY DIFFRACTION98.43
2.37-2.550.25141270.21432513X-RAY DIFFRACTION96.85
2.55-2.810.23431430.20512525X-RAY DIFFRACTION99.11
2.81-3.220.23581330.1882593X-RAY DIFFRACTION99.16
3.22-4.050.22811510.15732598X-RAY DIFFRACTION99.6
4.06-44.320.17231460.1432758X-RAY DIFFRACTION99.45
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)
12.69140908723-0.900282677494-0.4474766601281.42005263497-0.7150868830355.81675441831-0.05570151815080.0160794005386-0.3383922436970.1901572556380.0992543278747-0.0598858663650.341955401863-0.0429163341033-0.04643220120420.291610989201-0.0116987308778-0.04513639996280.2166849104990.01858254335740.307038344056-4.760902955541.64360747083-7.35367008935
21.77096457667-1.777728048990.2036771853052.77274513781-0.2162309896241.22643252035-0.0659256795742-0.182996022389-0.1048181823090.2223843894960.230355282321-0.08718780051260.05745246854150.0524861868355-0.1628041918560.204838224005-0.007958915819650.01544075808450.209501532942-0.01540180395450.172941668359-4.76755544889.3952575517-10.9365020256
35.18644119042-0.2750615962556.7383018971.4342664946-0.5037083760528.85997494794-0.260389970735-0.2568279579160.2982127496220.3130266651310.161798176317-0.00157310788913-0.247326522824-0.08719262102470.1135701826420.2636230827920.06425073208220.01908233171580.199347276408-0.02074416363920.225250747411-10.423355746127.0030543354-11.4248661273
43.64463123683-1.02688873497-0.2433253670033.789538305240.4556212225481.73639602417-0.0691036878435-0.02393320063440.08522155621420.007093748319940.0910260219097-0.402064887843-0.06250615886130.167802684811-0.03159572452360.1921434600460.0259720696914-0.01178174199690.1943408583560.01225688705830.186681533012-0.99316133435716.9661681765-16.0731281382
56.271321251182.949388990352.435411390656.072096969862.041206634653.60271025632-0.1361714493250.135796135401-0.073738835426-0.4103318359120.216028574933-0.4134516190340.07962361411970.404747326871-0.0710209776930.2384749168770.02249340051230.03969680806960.1966192992570.03701048840910.2019170753575.1504361698424.1256069653-28.1721001863
63.28484364150.319331172473-2.010155694871.69550253796-0.9348707880481.55625564708-0.0531641869930.336370969158-0.00286056494916-0.1367527535960.0997407102802-0.03675257854350.123307506415-0.193649292298-0.04032731295380.199592164361-0.0004265935367420.02453760806740.1815188068450.006216851956870.150751345335-7.7793068933626.1630081234-25.8325016784
70.621980619654-0.270090639613-0.8351398878193.594485935810.06406477435131.846475572720.1002895534690.3836254809210.230179002662-0.362936547281-0.0615756284533-0.277718042129-0.125324080743-0.34903919245-0.05246139728620.221891309764-0.0116062976915-0.01915966839480.2845479140040.04668658651950.178946159696-7.0884172950530.6131367287-33.4415683583
84.73494008357-0.806526340907-0.4913397072693.08400749656-0.3715260685176.006195631640.07742762694490.0232444011950.3994854643750.2289065026950.09677925754150.0996468479155-0.2211669615740.00301854681139-0.1504820375130.2419586834570.00981338541590.01701774052260.0900671578147-0.02140230966150.217096273266-8.0623273176936.5718057124-17.6530837813
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 421 )389 - 4211 - 33
22chain 'A' and (resid 422 through 494 )422 - 49434 - 106
33chain 'A' and (resid 495 through 514 )495 - 514107 - 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 602 )576 - 602188 - 214
77chain 'A' and (resid 603 through 623 )603 - 623215 - 235
88chain 'A' and (resid 624 through 658 )624 - 658236 - 270

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