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- PDB-5c3h: Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Pr... -

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Basic information

Entry
Database: PDB / ID: 5c3h
TitleFragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Compound 1
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 / cysteine-type endopeptidase inhibitor activity / protein K63-linked ubiquitination / negative regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of type I interferon production / 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 / Wnt signaling pathway / Regulation of PTEN stability and activity / 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 / 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. ...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
4-[2-oxo-2-(piperidin-1-yl)ethyl]piperazin-1-ium / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.65 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 17, 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)12,9643
Polymers12,6861
Non-polymers2782
Water1,20767
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area6550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.562, 71.562, 105.726
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number91
Space group name H-MP4122

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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-4XE / 4-[2-oxo-2-(piperidin-1-yl)ethyl]piperazin-1-ium


Mass: 212.312 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H22N3O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 67 / 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: 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 RAXIS / Detector: IMAGE PLATE / Date: Dec 8, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.65→28.9 Å / Num. all: 8179 / Num. obs: 8179 / % possible obs: 97.3 % / Observed criterion σ(I): 2.2 / Redundancy: 2.06 % / Biso Wilson estimate: 79.3 Å2 / Rmerge(I) obs: 0.368 / Net I/σ(I): 6.3
Reflection shellResolution: 2.65→2.84 Å / Rmerge(I) obs: 0.368 / Mean I/σ(I) obs: 2.2 / % possible all: 97.2

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
d*TREK9.9data reduction
d*TREKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OPY

2opy


Resolution: 2.65→28.9 Å / Cor.coef. Fo:Fc: 0.9311 / Cor.coef. Fo:Fc free: 0.9103 / SU R Cruickshank DPI: 0.257 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.282 / SU Rfree Blow DPI: 0.236 / SU Rfree Cruickshank DPI: 0.226
RfactorNum. reflection% reflectionSelection details
Rfree0.2488 434 5.31 %RANDOM
Rwork0.2051 ---
obs0.2073 8179 96.93 %-
Displacement parametersBiso mean: 67.677 Å2
Baniso -1Baniso -2Baniso -3
1--5.8151 Å20 Å20 Å2
2---5.8151 Å20 Å2
3---11.6302 Å2
Refine analyzeLuzzati coordinate error obs: 0.354 Å
Refinement stepCycle: LAST / Resolution: 2.65→28.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms866 0 16 67 949
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.01932HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.061288HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d313SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes25HARMONIC2
X-RAY DIFFRACTIONt_gen_planes136HARMONIC16
X-RAY DIFFRACTIONt_it932HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion5.99
X-RAY DIFFRACTIONt_other_torsion20.76
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_contact1070SEMIHARMONIC4
LS refinement shellResolution: 2.65→2.96 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.3039 117 5.28 %
Rwork0.2452 2101 -
all0.2484 2218 -
obs--95.52 %
Refinement TLS params.Method: refined / Origin x: -17.3703 Å / Origin y: -28.7623 Å / Origin z: -4.132 Å
111213212223313233
T-0.0812 Å2-0.0467 Å2-0.0033 Å2-0.0024 Å2-0.0528 Å2---0.098 Å2
L4.8521 °2-0.599 °2-0.0187 °2-0.9275 °2-0.9922 °2--2.1254 °2
S0.0615 Å °-0.1648 Å °0.1613 Å °0.1376 Å °-0.0499 Å °0.0094 Å °0.0847 Å °0.1386 Å °-0.0116 Å °
Refinement TLS groupSelection details: { A|249 - A|354 }

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