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- PDB-5c0k: Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Pr... -

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Basic information

Entry
Database: PDB / ID: 5c0k
TitleFragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Compound 3
ComponentsE3 ubiquitin-protein ligase XIAP
KeywordsAPOPTOSIS / ligase
Function / homology
Function and homology information


regulation of apoptosis involved in tissue homeostasis / positive regulation of protein linear polyubiquitination / copper ion homeostasis / regulation of BMP signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / nucleotide-binding oligomerization domain containing 1 signaling pathway / nucleotide-binding oligomerization domain containing 2 signaling pathway / SMAC, XIAP-regulated apoptotic response / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / Activation of caspases through apoptosome-mediated cleavage ...regulation of apoptosis involved in tissue homeostasis / positive regulation of protein linear polyubiquitination / copper ion homeostasis / regulation of BMP signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / nucleotide-binding oligomerization domain containing 1 signaling pathway / nucleotide-binding oligomerization domain containing 2 signaling pathway / SMAC, XIAP-regulated apoptotic response / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / Activation of caspases through apoptosome-mediated cleavage / Regulation of the apoptosome activity / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / regulation of innate immune response / protein K63-linked ubiquitination / positive regulation of type I interferon production / cysteine-type endopeptidase inhibitor activity / negative regulation of tumor necrosis factor-mediated signaling pathway / protein serine/threonine kinase binding / Regulation of PTEN localization / positive regulation of protein ubiquitination / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of JNK cascade / Deactivation of the beta-catenin transactivating complex / Regulation of TNFR1 signaling / RING-type E3 ubiquitin transferase / Regulation of necroptotic cell death / Regulation of PTEN stability and activity / Wnt signaling pathway / ubiquitin-protein transferase activity / ubiquitin protein ligase activity / positive regulation of canonical Wnt signaling pathway / regulation of inflammatory response / neuron apoptotic process / regulation of apoptotic process / response to lipopolysaccharide / positive regulation of canonical NF-kappaB signal transduction / regulation of cell cycle / defense response to bacterium / DNA damage response / negative regulation of apoptotic process / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
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. ...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-4WK / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsChessari, G. / Buck, I.M. / Day, J.E.H. / Day, P.J. / Iqbal, A. / Johnson, C.N. / Lewis, E.J. / Martins, V. / Miller, D. / Reader, M. ...Chessari, G. / Buck, I.M. / Day, J.E.H. / Day, P.J. / Iqbal, A. / Johnson, C.N. / Lewis, E.J. / Martins, V. / Miller, D. / Reader, M. / Rees, D.C. / Rich, S.J. / Tamanini, E. / Vitorino, M. / Ward, G.A. / Williams, P.A. / Williams, G. / Wilsher, N.E. / Woolford, A.J.-A.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP.
Authors: Chessari, G. / Buck, I.M. / Day, J.E. / Day, P.J. / Iqbal, A. / Johnson, C.N. / Lewis, E.J. / Martins, V. / Miller, D. / Reader, M. / Rees, D.C. / Rich, S.J. / Tamanini, E. / Vitorino, M. / ...Authors: Chessari, G. / Buck, I.M. / Day, J.E. / Day, P.J. / Iqbal, A. / Johnson, C.N. / Lewis, E.J. / Martins, V. / Miller, D. / Reader, M. / Rees, D.C. / Rich, S.J. / Tamanini, E. / Vitorino, M. / Ward, G.A. / Williams, P.A. / Williams, G. / Wilsher, N.E. / Woolford, A.J.
History
DepositionJun 12, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: 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: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,0645
Polymers12,6861
Non-polymers3784
Water2,270126
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint3 kcal/mol
Surface area6350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.430, 71.430, 104.990
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number91
Space group name H-MP4122
Components on special symmetry positions
IDModelComponents
11A-604-

HOH

21A-605-

HOH

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Components

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


Mass: 12686.206 Da / Num. of mol.: 1 / Fragment: residues 249-354
Source method: isolated from a genetically manipulated source
Details: Image clone / Source: (gene. exp.) Homo sapiens (human) / Gene: XIAP, API3, BIRC4, IAP3 / Plasmid: pET 28b / Production host: Escherichia coli BL21(DE3) (bacteria)
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.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-4WK / (2S)-1-{[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]amino}-1-oxopropan-2-aminium


Mass: 188.247 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.32 Å3/Da / Density meas: 1.35 Mg/m3 / Density % sol: 47 % / Description: Blocks
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 3.9M NaCl, 0.1M HEPES/NaOH pH=7.5 / PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 11, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.2→27.29 Å / Num. all: 14177 / Num. obs: 14177 / % possible obs: 98.5 % / Observed criterion σ(I): 2 / Redundancy: 3.58 % / Biso Wilson estimate: 60.57 Å2 / Rmerge(I) obs: 0.066 / Net I/σ(I): 8.6
Reflection shellResolution: 2.2→2.28 Å / Rmerge(I) obs: 0.392 / Mean I/σ(I) obs: 2 / % possible all: 99.2

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
d*TREKdata reduction
d*TREKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OPY

2opy


Resolution: 2.2→27.29 Å / Cor.coef. Fo:Fc: 0.9484 / Cor.coef. Fo:Fc free: 0.9397 / SU R Cruickshank DPI: 0.139 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.156 / SU Rfree Blow DPI: 0.141 / SU Rfree Cruickshank DPI: 0.131
RfactorNum. reflection% reflectionSelection details
Rfree0.2239 767 5.41 %RANDOM
Rwork0.2016 ---
obs0.2028 14177 98.47 %-
Displacement parametersBiso mean: 62.5 Å2
Baniso -1Baniso -2Baniso -3
1--2.3183 Å20 Å20 Å2
2---2.3183 Å20 Å2
3---4.6366 Å2
Refine analyzeLuzzati coordinate error obs: 0.289 Å
Refinement stepCycle: LAST / Resolution: 2.2→27.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms847 0 22 126 995
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012911HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.041245HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d298SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes24HARMONIC2
X-RAY DIFFRACTIONt_gen_planes135HARMONIC16
X-RAY DIFFRACTIONt_it911HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion5.99
X-RAY DIFFRACTIONt_other_torsion19.79
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion106SEMIHARMONIC5
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_contact1129SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.38 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2891 142 4.95 %
Rwork0.2482 2729 -
all0.25 2871 -
obs--99.14 %
Refinement TLS params.Method: refined / Origin x: -17.073 Å / Origin y: -29.2196 Å / Origin z: -4.1285 Å
111213212223313233
T-0.1532 Å2-0.0203 Å2-0.035 Å2--0.0668 Å2-0.0839 Å2---0.1346 Å2
L4.4069 °2-0.6779 °20.076 °2-0.9254 °2-1.2092 °2--1.2816 °2
S0.1697 Å °-0.3399 Å °0.0073 Å °0.0686 Å °-0.0489 Å °-0.0639 Å °0.0722 Å °0.0535 Å °-0.1209 Å °
Refinement TLS groupSelection details: { A|249 - A|352 }

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