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- PDB-4kju: Crystal structure of XIAP-Bir2 with a bound benzodiazepinone inhi... -

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Basic information

Entry
Database: PDB / ID: 4kju
TitleCrystal structure of XIAP-Bir2 with a bound benzodiazepinone inhibitor.
ComponentsE3 ubiquitin-protein ligase XIAP
KeywordsAPOPTOSIS/APOPTOSIS INHIBITOR / XIAP inhibitors / BIR2 / benzodiazepinone / oncology / caspase / APOPTOSIS-APOPTOSIS INHIBITOR complex
Function / homology
Function and homology information


copper ion homeostasis / inhibition of cysteine-type endopeptidase activity involved in apoptotic process / regulation of BMP signaling pathway / positive regulation of protein linear polyubiquitination / regulation of nucleotide-binding oligomerization domain containing signaling pathway / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / Activation of caspases through apoptosome-mediated cleavage / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / SMAC (DIABLO) binds to IAPs ...copper ion homeostasis / inhibition of cysteine-type endopeptidase activity involved in apoptotic process / regulation of BMP signaling pathway / positive regulation of protein linear polyubiquitination / regulation of nucleotide-binding oligomerization domain containing signaling pathway / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / Activation of caspases through apoptosome-mediated cleavage / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / SMAC (DIABLO) binds to IAPs / RIPK1-mediated regulated necrosis / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / regulation of innate immune response / Regulation of PTEN localization / positive regulation of protein ubiquitination / TNFR1-induced NFkappaB signaling pathway / Regulation of TNFR1 signaling / Deactivation of the beta-catenin transactivating complex / RING-type E3 ubiquitin transferase / spindle microtubule / Regulation of necroptotic cell death / Wnt signaling pathway / ubiquitin protein ligase activity / Regulation of PTEN stability and activity / ubiquitin-protein transferase activity / positive regulation of canonical Wnt signaling pathway / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / neuron apoptotic process / regulation of cell population proliferation / regulation of inflammatory response / regulation of cell cycle / cellular response to DNA damage stimulus / negative regulation of apoptotic process / nucleoplasm / identical protein binding / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
XIAP/BIRC8, UBA domain / BIR repeat. / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / BIR repeat / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / Inhibitor of Apoptosis domain / Death-like domain superfamily / Ring finger ...XIAP/BIRC8, UBA domain / BIR repeat. / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / BIR repeat / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / Inhibitor of Apoptosis domain / Death-like domain superfamily / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-1RH / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.6 Å
AuthorsLukacs, C.M. / Janson, C.A.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Optimization of Benzodiazepinones as Selective Inhibitors of the X-Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain.
Authors: Kester, R.F. / Donnell, A.F. / Lou, Y. / Remiszewski, S.W. / Lombardo, L.J. / Chen, S. / Le, N.T. / Lo, J. / Moliterni, J.A. / Han, X. / Hogg, J.H. / Liang, W. / Michoud, C. / Rupert, K.C. / ...Authors: Kester, R.F. / Donnell, A.F. / Lou, Y. / Remiszewski, S.W. / Lombardo, L.J. / Chen, S. / Le, N.T. / Lo, J. / Moliterni, J.A. / Han, X. / Hogg, J.H. / Liang, W. / Michoud, C. / Rupert, K.C. / Mischke, S. / Le, K. / Weisel, M. / Janson, C.A. / Lukacs, C.M. / Fretland, A.J. / Hong, K. / Polonskaia, A. / Gao, L. / Li, S. / Solis, D.S. / Aguilar, D. / Tardell, C. / Dvorozniak, M. / Tannu, S. / Lee, E.C. / Schutt, A.D. / Goggin, B.
History
DepositionMay 3, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2014Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase XIAP
C: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5555
Polymers19,8722
Non-polymers6823
Water1,892105
1
A: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,5533
Polymers9,9361
Non-polymers6172
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,0022
Polymers9,9361
Non-polymers651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)75.667, 75.667, 109.105
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422
Detailsmonomer

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Components

#1: Protein E3 ubiquitin-protein ligase XIAP / Baculoviral IAP repeat-containing protein 4 / IAP-like protein / ILP / hILP / Inhibitor of ...Baculoviral IAP repeat-containing protein 4 / IAP-like protein / ILP / hILP / Inhibitor of apoptosis protein 3 / IAP-3 / hIAP-3 / hIAP3 / X-linked inhibitor of apoptosis protein / X-linked IAP


Mass: 9936.131 Da / Num. of mol.: 2 / Fragment: XIAP-Bir2 (unp residues 152-236) / Mutation: C202A, C213G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: XIAP, API3, BIRC4, IAP3 / Plasmid: pET28A / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2(DE3)PLysS
References: UniProt: P98170, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-1RH / N-{(3S)-5-(4-aminobenzoyl)-1-[(2-methoxynaphthalen-1-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}-N~2~-methyl-L-alaninamide


Mass: 551.636 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H33N5O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 105 / Source method: isolated from a natural source / Formula: H2O

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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: 1.96 Å3/Da / Density % sol: 37.39 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 1.5 M ammonium sulfate, 125 mM Bis-tris-propane , pH 7.0, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99987 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 30, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.6→38.2 Å / Num. obs: 21271 / % possible obs: 99.9 % / Redundancy: 12.4 % / Biso Wilson estimate: 21.64 Å2 / Rsym value: 0.058 / Net I/σ(I): 22.9
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 13 % / Rmerge(I) obs: 0.423 / Mean I/σ(I) obs: 5.7 / Num. unique all: 3045 / % possible all: 100

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Processing

Software
NameVersionClassification
CCP4model building
REFMAC5.7.0032refinement
XDSdata reduction
SCALAdata scaling
CCP4phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4J3Y
Resolution: 1.6→38.2 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.953 / SU B: 1.866 / SU ML: 0.065 / Cross valid method: THROUGHOUT / ESU R: 0.092 / ESU R Free: 0.093 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21334 1110 5.2 %RANDOM
Rwork0.17953 ---
obs0.18119 20153 99.88 %-
all-21263 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.276 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å20 Å20 Å2
2--0.03 Å2-0 Å2
3----0.07 Å2
Refinement stepCycle: LAST / Resolution: 1.6→38.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1287 0 43 105 1435
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0191377
X-RAY DIFFRACTIONr_bond_other_d0.0040.021212
X-RAY DIFFRACTIONr_angle_refined_deg1.8761.9521868
X-RAY DIFFRACTIONr_angle_other_deg0.9823.0092772
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5395156
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.4922.46673
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.18915196
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6541512
X-RAY DIFFRACTIONr_chiral_restr0.1180.2169
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211595
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02385
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.284 79 -
Rwork0.252 1464 -
obs--99.94 %

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