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- PDB-5c7a: Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Pr... -

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Basic information

Entry
Database: PDB / ID: 5c7a
TitleFragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Compound 7
ComponentsE3 ubiquitin-protein ligase XIAP
KeywordsAPOPTOSIS / ligase
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-4YE / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.36 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 24, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,0123
Polymers12,6861
Non-polymers3262
Water2,126118
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area6570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.401, 71.401, 105.242
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-599-

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: UNP 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-4YE / (2R)-4-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-2-methylpiperazin-1-ium


Mass: 260.355 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H22N3O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 118 / 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: block
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1M Hepes-NaOH 7.5, 3.9M NaCL / PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 70 / Detector: CCD / Date: Apr 10, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.36→59.08 Å / Num. obs: 11692 / % possible obs: 96.4 % / Observed criterion σ(I): 2 / Redundancy: 2.2 % / Rmerge(I) obs: 0.047 / Net I/σ(I): 3.3
Reflection shellResolution: 2.36→2.5 Å / Rmerge(I) obs: 0.269 / Mean I/σ(I) obs: 3.6 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0107refinement
d*TREKdata reduction
d*TREKdata scaling
PHASERphasing
RefinementResolution: 2.36→59.08 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.88 / SU B: 10.078 / SU ML: 0.141 / Cross valid method: THROUGHOUT / ESU R: 0.209 / ESU R Free: 0.199 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.26442 620 5.5 %RANDOM
Rwork0.21899 ---
obs0.22141 10596 95.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.267 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å2-0 Å2-0 Å2
2--0 Å2-0 Å2
3----0.01 Å2
Refinement stepCycle: 1 / Resolution: 2.36→59.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms866 0 20 118 1004
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.019915
X-RAY DIFFRACTIONr_bond_other_d0.0040.02522
X-RAY DIFFRACTIONr_angle_refined_deg1.4651.9171242
X-RAY DIFFRACTIONr_angle_other_deg0.2110.95852
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7495105
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.2242449
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.30815.1150
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.192154
X-RAY DIFFRACTIONr_chiral_restr0.1260.2119
X-RAY DIFFRACTIONr_gen_planes_refined00.022727
X-RAY DIFFRACTIONr_gen_planes_other00.0144
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_it1.7174.77423
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.4865.229491
X-RAY DIFFRACTIONr_scbond_other2.4845.23492
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.66911.083308
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.365→2.426 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 41 -
Rwork0.289 677 -
obs--85.68 %
Refinement TLS params.Method: refined / Origin x: -17.3268 Å / Origin y: -28.5367 Å / Origin z: -4.0141 Å
111213212223313233
T0.0733 Å2-0.0098 Å20.0069 Å2-0.1087 Å2-0.025 Å2--0.013 Å2
L5.7786 °20.2476 °21.4962 °2-2.871 °2-0.7244 °2--4.3483 °2
S0.1232 Å °-0.4121 Å °0.0529 Å °0.2612 Å °-0.0437 Å °0.1345 Å °-0.0783 Å °-0.0502 Å °-0.0795 Å °

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