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- PDB-6w8i: Ternary complex structure - BTK cIAP compound 15 -

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Basic information

Entry
Database: PDB / ID: 6w8i
TitleTernary complex structure - BTK cIAP compound 15
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 / regulation of cysteine-type endopeptidase activity / 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 necroptotic process / regulation of B cell cytokine production / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway ...negative regulation of ripoptosome assembly involved in necroptotic process / regulation of cysteine-type endopeptidase activity / 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 necroptotic process / regulation of B cell cytokine production / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / positive regulation of protein K63-linked ubiquitination / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / 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 / XY body / negative regulation of necroptotic process / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / cellular response to interleukin-7 / MyD88 deficiency (TLR2/4) / positive regulation of protein monoubiquitination / regulation of reactive oxygen species metabolic process / TNFR1-induced proapoptotic signaling / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / positive regulation of immunoglobulin production / RIPK1-mediated regulated necrosis / 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 / regulation of toll-like receptor signaling pathway / regulation of innate immune response / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / non-canonical NF-kappaB signal transduction / regulation of cell differentiation / necroptotic process / Fc-epsilon receptor signaling pathway / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / RHO GTPases Activate WASPs and WAVEs / canonical NF-kappaB signal transduction / positive regulation of B cell proliferation / positive regulation of phagocytosis / cell maturation / response to cAMP / tumor necrosis factor-mediated signaling pathway / FCERI mediated Ca+2 mobilization / TICAM1, RIP1-mediated IKK complex recruitment / IKK complex recruitment mediated by RIP1 / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / TNFR1-induced NF-kappa-B signaling pathway / ubiquitin binding / positive regulation of protein ubiquitination / TNFR2 non-canonical NF-kB pathway / calcium-mediated signaling / apoptotic signaling pathway / Regulation of TNFR1 signaling / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / RING-type E3 ubiquitin transferase / NOD1/2 Signaling Pathway / placenta development / Regulation of necroptotic cell death / cytoplasmic side of plasma membrane / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / cellular response to reactive oxygen species / peptidyl-tyrosine phosphorylation / protein polyubiquitination / ubiquitin-protein transferase activity / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / ubiquitin protein ligase activity / G alpha (12/13) signalling events / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / regulation of cell population proliferation / ER-Phagosome pathway / protein-folding chaperone binding / transferase activity / regulation of inflammatory response / cytoplasmic vesicle / G alpha (q) signalling events
Similarity search - Function
BIRC2/BIRC3, UBA domain / : / BIRC2/3-like, UBA domain / Caspase recruitment domain / BIR repeat. / Tyrosine-protein kinase BTK, SH3 domain / BIR repeat / Zinc finger, Btk motif / Inhibitor of Apoptosis domain / BTK motif ...BIRC2/BIRC3, UBA domain / : / BIRC2/3-like, UBA domain / Caspase recruitment domain / BIR repeat. / Tyrosine-protein kinase BTK, SH3 domain / BIR repeat / Zinc finger, Btk motif / Inhibitor of Apoptosis domain / BTK motif / BIR repeat profile. / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / 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 / Ring finger / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH3 domain / Zinc finger RING-type profile. / Zinc finger, RING-type / 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-TKY / Tyrosine-protein kinase BTK / Baculoviral IAP repeat-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.8 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 20, 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

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
B: Tyrosine-protein kinase BTK
C: Tyrosine-protein kinase BTK
D: Baculoviral IAP repeat-containing protein 2
E: Baculoviral IAP repeat-containing protein 2
F: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,03212
Polymers130,2956
Non-polymers3,7376
Water00
1
A: Tyrosine-protein kinase BTK
D: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,6774
Polymers43,4322
Non-polymers1,2462
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase BTK
E: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,6774
Polymers43,4322
Non-polymers1,2462
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase BTK
F: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,6774
Polymers43,4322
Non-polymers1,2462
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)69.250, 109.490, 188.740
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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.: 3
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.: 3
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-TKY / 14-{[(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}-3,6,9,12-tetraoxatetradecan-1-yl (3R)-3-{5-amino-4-carbamoyl-3-[4-(2,4-difluorophenoxy)phenyl]-1H-pyrazol-1-yl}piperidine-1-carboxylate


Mass: 1180.341 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C62H79F2N9O12 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
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: 2.75 Å3/Da / Density % sol: 55.2 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 24% PEG3350, 0.2 M Sodium Formate pH 7, 200 mM Sodium Chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.8→50 Å / Num. obs: 14726 / % possible obs: 100 % / Redundancy: 6.6 % / Biso Wilson estimate: 32.8 Å2 / CC1/2: 0.98 / Rpim(I) all: 0.152 / Net I/σ(I): 5.7
Reflection shellResolution: 3.8→3.813 Å / Mean I/σ(I) obs: 2.5 / Num. unique obs: 156 / CC1/2: 0.7 / Rpim(I) all: 0.368

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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: 3.8→49.74 Å / Cor.coef. Fo:Fc: 0.851 / Cor.coef. Fo:Fc free: 0.805 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.713
RfactorNum. reflection% reflectionSelection details
Rfree0.251 745 5.06 %RANDOM
Rwork0.211 ---
obs0.213 14726 100 %-
Displacement parametersBiso max: 203.01 Å2 / Biso mean: 51.85 Å2 / Biso min: 14.75 Å2
Baniso -1Baniso -2Baniso -3
1-21.7859 Å20 Å20 Å2
2--2.3406 Å20 Å2
3----24.1265 Å2
Refine analyzeLuzzati coordinate error obs: 0.52 Å
Refinement stepCycle: final / Resolution: 3.8→49.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8206 0 258 0 8464
Biso mean--54.11 --
Num. residues----1044
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2982SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1583HARMONIC5
X-RAY DIFFRACTIONt_it8455HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1085SEMIHARMONIC5
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_contact9641SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8731HARMONIC20.007
X-RAY DIFFRACTIONt_angle_deg11854HARMONIC20.91
X-RAY DIFFRACTIONt_omega_torsion1.75
X-RAY DIFFRACTIONt_other_torsion20.37
LS refinement shellResolution: 3.8→3.94 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.309 64 4.7 %
Rwork0.246 1368 -
obs--99.9 %
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)
10.20890.08020.068600.15560.24180.00060.00020.00590.0012-0.00180.0066-0.00730.01480.0012-0.00510.00290.00060.002-0.0035-0.0056-27.7277-8.139131.7082
20.2705-0.10670.0050.1337-0.02050.0265-0.00090.0084-0.0006-0.01680.00770.00120.00240.0072-0.0068-0.00470.00720.003-0.00020.00450.0047-53.232-44.034517.1726
30.14920.1410.05890.2383-0.09010.08710.0022-0.0004-0.00210.0011-0.0013-0.0010.00460.008-0.00090.0021-0.0076-0.0029-0.0048-0.01030.001-53.3085-17.743465.5074
40.18770.1371-0.12210.06860.05290.20820.00020.0028-0.00050.0052-0-0.0002-0.00320.0004-0.00020.00210.00070.00290.00450.00270.001-17.2128-38.588318.154
50.19290.03090.30760.0525-0.08990.0679-0.00030.0018-0.00120.0002-0.0011-0.00040.00370.00140.0014-0.00250.0106-0.00410.00390.0055-0.0017-63.317-12.37827.6133
60.05980.03-0.01250.04540.066300-0.00240.00110.0010.0010.00360.00220.002-0.0011-0.0045-0.0018-0.0014-0.002-0.01120.0013-84.0217-38.4372.967
70.0380.06810.04160.0614-0.23650.0873-0.00010.0039-0.0014-0.00270.00070-0.00170.0014-0.00060.0012-0.0017-0.00120.00090.00170.0005-50.7433-24.769835.4723
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|393 - A|657 }A393 - 657
2X-RAY DIFFRACTION2{ B|395 - B|657 }B395 - 657
3X-RAY DIFFRACTION3{ C|395 - C|657 }C395 - 657
4X-RAY DIFFRACTION4{ D|260 - D|351 D|501 - D|501 }D260 - 351
5X-RAY DIFFRACTION4{ D|260 - D|351 D|501 - D|501 }D501
6X-RAY DIFFRACTION5{ E|260 - E|352 E|501 - E|501 }E260 - 352
7X-RAY DIFFRACTION5{ E|260 - E|352 E|501 - E|501 }E501
8X-RAY DIFFRACTION6{ F|260 - F|352 F|501 - F|501 }F260 - 352
9X-RAY DIFFRACTION6{ F|260 - F|352 F|501 - F|501 }F501
10X-RAY DIFFRACTION7{ C|701 - C|701 E|502 - E|502 D|502 - D|502 }C701
11X-RAY DIFFRACTION7{ C|701 - C|701 E|502 - E|502 D|502 - D|502 }E502
12X-RAY DIFFRACTION7{ C|701 - C|701 E|502 - E|502 D|502 - D|502 }D502

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