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- PDB-6w7o: Ternary complex structure - BTK cIAP compound 17 -

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Basic information

Entry
Database: PDB / ID: 6w7o
TitleTernary complex structure - BTK cIAP compound 17
Components
  • Baculoviral IAP repeat-containing protein 2
  • Tyrosine-protein kinase BTK
KeywordsLIGASE/TRANSFERASE / cIAP E3 PROTAC / LIGASE / LIGASE-TRANSFERASE complex
Function / homology
Function and homology information


negative regulation of ripoptosome assembly involved in necroptotic process / FBXO family protein binding / regulation of RIG-I signaling pathway / positive regulation of protein K48-linked ubiquitination / regulation of non-canonical NF-kappaB signal transduction / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of B cell cytokine production / regulation of necroptotic process / regulation of B cell apoptotic process / positive regulation of protein K63-linked ubiquitination ...negative regulation of ripoptosome assembly involved in necroptotic process / FBXO family protein binding / regulation of RIG-I signaling pathway / positive regulation of protein K48-linked ubiquitination / regulation of non-canonical NF-kappaB signal transduction / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of B cell cytokine production / regulation of necroptotic process / regulation of B cell apoptotic process / positive regulation of protein K63-linked ubiquitination / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / proteoglycan catabolic process / CD40 receptor complex / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / positive regulation of cGAS/STING signaling pathway / cellular response to molecule of fungal origin / negative regulation of necroptotic process / XY body / positive regulation of type I hypersensitivity / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / non-canonical NF-kappaB signal transduction / TNFR1-induced proapoptotic signaling / positive regulation of protein monoubiquitination / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / RIPK1-mediated regulated necrosis / regulation of reactive oxygen species metabolic process / positive regulation of B cell differentiation / positive regulation of immunoglobulin production / phospholipase activator activity / regulation of toll-like receptor signaling pathway / regulation of innate immune response / negative regulation of interleukin-10 production / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / positive regulation of NLRP3 inflammasome complex assembly / Fc-epsilon receptor signaling pathway / mesoderm development / necroptotic process / phosphatidylinositol-3,4,5-trisphosphate binding / B cell activation / regulation of cell differentiation / response to cAMP / canonical NF-kappaB signal transduction / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / cell maturation / positive regulation of B cell proliferation / FCERI mediated Ca+2 mobilization / positive regulation of phagocytosis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / peptidyl-tyrosine phosphorylation / TICAM1, RIP1-mediated IKK complex recruitment / placenta development / IKK complex recruitment mediated by RIP1 / ubiquitin binding / positive regulation of protein ubiquitination / tumor necrosis factor-mediated signaling pathway / TNFR1-induced NF-kappa-B signaling pathway / cellular response to reactive oxygen species / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / TNFR2 non-canonical NF-kB pathway / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / apoptotic signaling pathway / Regulation of TNFR1 signaling / calcium-mediated signaling / positive regulation of NF-kappaB transcription factor activity / NOD1/2 Signaling Pathway / RING-type E3 ubiquitin transferase / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / positive regulation of interleukin-6 production / cytoplasmic side of plasma membrane / protein polyubiquitination / G beta:gamma signalling through BTK / ubiquitin-protein transferase activity / positive regulation of tumor necrosis factor production / ubiquitin protein ligase activity / DAP12 signaling / G alpha (12/13) signalling events / T cell receptor signaling pathway / regulation of cell population proliferation / protein-folding chaperone binding / transferase activity / ER-Phagosome pathway / regulation of inflammatory response / cytoplasmic vesicle / protein tyrosine kinase activity
Similarity search - Function
BIRC2/BIRC3, UBA domain / : / BIRC2/3-like, UBA domain / : / Caspase recruitment domain / BIR repeat. / Tyrosine-protein kinase BTK, SH3 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. ...BIRC2/BIRC3, UBA domain / : / BIRC2/3-like, UBA domain / : / Caspase recruitment domain / BIR repeat. / Tyrosine-protein kinase BTK, SH3 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Zinc finger, C3HC4 type (RING finger) / PH domain / : / Death-like domain superfamily / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Ring finger / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / Zinc finger RING-type profile. / SH2 domain / Zinc finger, RING-type / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-TL7 / Tyrosine-protein kinase BTK / Baculoviral IAP repeat-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 Å
AuthorsCalabrese, M.F. / Schiemer, J.S.
CitationJournal: Nat.Chem.Biol. / Year: 2020
Title: Structural Characterization of BTK:PROTAC:cIAP Ternary Complexes: From Snapshots to Ensembles
Authors: Calabrese, M.F. / Schiemer, J.S. / Horst, R. / Meng, Y. / Montgomery, J. / Xu, Y. / Feng, X. / Borzilleri, K. / Uccello, D.P. / Leverett, C. / Brown, S. / Che, Y. / Brown, M.F. / Hayward, M. ...Authors: Calabrese, M.F. / Schiemer, J.S. / Horst, R. / Meng, Y. / Montgomery, J. / Xu, Y. / Feng, X. / Borzilleri, K. / Uccello, D.P. / Leverett, C. / Brown, S. / Che, Y. / Brown, M.F. / Hayward, M.M. / Gilbert, A.M. / Noe, M.C.
History
DepositionMar 19, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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
B: Tyrosine-protein kinase BTK
C: Baculoviral IAP repeat-containing protein 2
D: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,1588
Polymers86,8634
Non-polymers2,2954
Water7,296405
1
A: Tyrosine-protein kinase BTK
C: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5794
Polymers43,4322
Non-polymers1,1482
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase BTK
D: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5794
Polymers43,4322
Non-polymers1,1482
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.980, 56.330, 98.120
Angle α, β, γ (deg.)104.980, 100.890, 90.130
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 32112.816 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Protein Baculoviral IAP repeat-containing protein 2 / Cellular inhibitor of apoptosis 1 / C-IAP1 / IAP homolog B / Inhibitor of apoptosis protein 2 / ...Cellular inhibitor of apoptosis 1 / C-IAP1 / IAP homolog B / Inhibitor of apoptosis protein 2 / hIAP2 / RING finger protein 48 / RING-type E3 ubiquitin transferase BIRC2 / TNFR2-TRAF-signaling complex protein 2


Mass: 11318.731 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC2, API1, MIHB, RNF48 / Production host: Escherichia coli (E. coli)
References: UniProt: Q13490, RING-type E3 ubiquitin transferase
#3: Chemical ChemComp-TL7 / [5-({[(3S)-2-(N-methyl-L-alanyl-3-methyl-L-valyl)-3-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]oxy}methyl)pyrazin-2-yl]methyl (3R)-3-{5-amino-4-carbamoyl-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazol-1-yl}piperidine-1-carboxylate


Mass: 1082.202 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C58H65F2N11O8 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 405 / 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: 2.29 Å3/Da / Density % sol: 46.27 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.7
Details: 50 mM ammonium sulfate, 100 mM Bis-Tris pH 6.7, 29% PE15/4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 26, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.17→94 Å / Num. obs: 38604 / % possible obs: 94.6 % / Redundancy: 1.8 % / Biso Wilson estimate: 33.06 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.078 / Net I/σ(I): 6.8
Reflection shellResolution: 2.17→2.18 Å / Num. unique obs: 414 / CC1/2: 0.76

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4KMN; 5P9J

4kmn

5p9j


Resolution: 2.17→54.34 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.873 / SU R Cruickshank DPI: 0.292 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.294 / SU Rfree Blow DPI: 0.211 / SU Rfree Cruickshank DPI: 0.212
RfactorNum. reflection% reflectionSelection details
Rfree0.24 1895 4.91 %RANDOM
Rwork0.196 ---
obs0.198 38603 94.6 %-
Displacement parametersBiso max: 121.42 Å2 / Biso mean: 35.9 Å2 / Biso min: 9.56 Å2
Baniso -1Baniso -2Baniso -3
1-4.2655 Å2-3.5168 Å2-2.5636 Å2
2--0.9012 Å21.0484 Å2
3----5.1667 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 2.17→54.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5677 0 160 405 6242
Biso mean--41.05 36.28 -
Num. residues----709
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2096SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1099HARMONIC5
X-RAY DIFFRACTIONt_it6001HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion732SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7265SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6001HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg8126HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion2.38
X-RAY DIFFRACTIONt_other_torsion17.52
LS refinement shellResolution: 2.17→2.247 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.286 160 5.1 %
Rwork0.275 3116 -
obs--94.4 %
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)
11.6457-0.035-0.16310.52280.06770.7516-0.0295-0.120.06010.05650.00750.03480.0197-0.01990.022-0.0787-0.0182-0.127-0.14020.00090.060514.790431.3508-11.3046
21.47480.0320.0010.4664-0.02150.6756-0.0120.1112-0.0131-0.0504-0.0169-0.01180.03590.05270.0289-0.0814-0.0123-0.1172-0.126-0.01910.06716.548628.6709-60.5493
30.79140.71231.17991.7752.16413.08250.0404-0.0708-0.0680.01940.0512-0.2573-0.1447-0.1821-0.0916-0.1411-0.0298-0.1124-0.19570.03970.169324.993955.401-19.7755
40.882-0.83751.52551.7674-2.33424.14960.05020.059-0.0882-0.09130.02650.225-0.1290.1394-0.0767-0.1438-0.0159-0.1078-0.2081-0.02480.14946.241453.2915-51.7141
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|396 - A|656 }A396 - 656
2X-RAY DIFFRACTION2{ B|396 - B|658 }B396 - 658
3X-RAY DIFFRACTION3{ C|258 - C|350 C|401 - C|401 }C258 - 350
4X-RAY DIFFRACTION3{ C|258 - C|350 C|401 - C|401 }C401
5X-RAY DIFFRACTION4{ D|258 - D|349 D|401 - D|401 }D258 - 349
6X-RAY DIFFRACTION4{ D|258 - D|349 D|401 - D|401 }D401

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