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- PDB-4kjv: Crystal structure of XIAP-Bir2 with a bound spirocyclic benzoxaze... -

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Basic information

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


endopeptidase regulator activity / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / copper ion homeostasis / nucleotide-binding oligomerization domain containing 1 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / protein serine/threonine kinase binding / nucleotide-binding oligomerization domain containing 2 signaling pathway ...endopeptidase regulator activity / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / copper ion homeostasis / nucleotide-binding oligomerization domain containing 1 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / protein serine/threonine kinase binding / nucleotide-binding oligomerization domain containing 2 signaling pathway / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / Activation of caspases through apoptosome-mediated cleavage / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / TNFR1-induced proapoptotic signaling / regulation of innate immune response / RIPK1-mediated regulated necrosis / cysteine-type endopeptidase inhibitor activity / protein K63-linked ubiquitination / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / positive regulation of type I interferon production / negative regulation of tumor necrosis factor-mediated signaling pathway / Regulation of PTEN localization / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of protein ubiquitination / Deactivation of the beta-catenin transactivating complex / Regulation of TNFR1 signaling / positive regulation of JNK cascade / RING-type E3 ubiquitin transferase / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / Regulation of necroptotic cell death / Wnt signaling pathway / Regulation of PTEN stability and activity / ubiquitin-protein transferase activity / positive regulation of canonical Wnt signaling pathway / ubiquitin protein ligase activity / regulation of cell population proliferation / regulation of inflammatory response / neuron apoptotic process / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / regulation of cell cycle / defense response to bacterium / DNA damage response / negative regulation of apoptotic process / nucleoplasm / identical protein binding / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
XIAP/BIRC8, UBA domain / : / BIRC2/3-like, UBA domain / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat ...XIAP/BIRC8, UBA domain / : / BIRC2/3-like, UBA domain / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / Inhibitor Of Apoptosis Protein (2mihbC-IAP-1); Chain A / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / Zinc finger, C3HC4 type (RING finger) / Death-like domain superfamily / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-1RK / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.7 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
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)20,5515
Polymers19,8722
Non-polymers6783
Water1,802100
1
A: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,5493
Polymers9,9361
Non-polymers6132
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
Length a, b, c (Å)74.196, 74.196, 108.564
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422

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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-1RK / 6-methoxy-5-({(3S)-3-[(N-methyl-L-alanyl)amino]-4-oxo-2',3,3',4,5',6'-hexahydro-5H-spiro[1,5-benzoxazepine-2,4'-pyran]-5-yl}methyl)naphthalene-2-carboxylic acid


Mass: 547.599 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H33N3O7
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 1.88 Å3/Da / Density % sol: 34.56 %
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

Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Jan 12, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.7→37.7 Å / Num. obs: 16849 / % possible obs: 98.8 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.038 / Net I/σ(I): 17
Reflection shellResolution: 1.7→1.76 Å / Redundancy: 3.16 % / Rmerge(I) obs: 0.371 / Mean I/σ(I) obs: 2.8 / Num. unique all: 1664

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Processing

Software
NameVersionClassification
CrystalCleardata collection
CCP4model building
REFMAC5.7.0032refinement
d*TREKdata reduction
d*TREKdata scaling
CCP4phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3J3Y

3j3y


Resolution: 1.7→37.13 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.945 / SU B: 5.288 / SU ML: 0.085 / Cross valid method: THROUGHOUT / ESU R: 0.127 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23789 885 5.3 %RANDOM
Rwork0.19415 ---
obs0.19636 15961 98.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.403 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å20 Å20 Å2
2--0.03 Å2-0 Å2
3----0.06 Å2
Refinement stepCycle: LAST / Resolution: 1.7→37.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1298 0 42 100 1440
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0191387
X-RAY DIFFRACTIONr_bond_other_d0.0050.021224
X-RAY DIFFRACTIONr_angle_refined_deg1.7481.951882
X-RAY DIFFRACTIONr_angle_other_deg0.9433.012802
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4975157
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.38222.29774
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.80515199
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1391513
X-RAY DIFFRACTIONr_chiral_restr0.1090.2171
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211596
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02383
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: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.461 66 -
Rwork0.442 1065 -
obs--91.21 %
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)
10.28140.0373-0.0012.94770.50220.61350.07280.00680.03650.0177-0.11830.01130.0398-0.0180.04550.0332-0.01220.01860.04150.00920.023417.697634.479916.0337
20.692-0.1903-0.01651.1662-1.25341.7084-0.0241-0.0501-0.012-0.17210.0063-0.00360.2688-0.07990.01780.0872-0.0302-0.00660.04450.01220.016717.85288.002712.1789
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A151 - 233
2X-RAY DIFFRACTION1A501
3X-RAY DIFFRACTION2C159 - 234

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