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- PDB-5c0l: Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Pr... -

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Basic information

Entry
Database: PDB / ID: 5c0l
TitleFragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Compound 2
ComponentsE3 ubiquitin-protein ligase XIAP
KeywordsLIGASE
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
4-(4-bromo-1H-pyrazol-1-yl)piperidinium / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.6 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 1.2May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)12,9833
Polymers12,6861
Non-polymers2972
Water1,00956
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area6670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.571, 71.571, 105.666
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-541-

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 245-354
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-4WJ / 4-(4-bromo-1H-pyrazol-1-yl)piperidinium


Mass: 231.113 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H13BrN3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 56 / 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/NaOHpH=7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9834 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 8, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9834 Å / Relative weight: 1
ReflectionResolution: 2.59→71.57 Å / Num. all: 8972 / Num. obs: 8972 / % possible obs: 99.5 % / Observed criterion σ(I): 2 / Redundancy: 3.6 % / Rmerge(I) obs: 0.071 / Net I/σ(I): 7.8
Reflection shellResolution: 2.59→2.63 Å / Rmerge(I) obs: 0.335 / Mean I/σ(I) obs: 2.2 / % possible all: 99.5

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Processing

SoftwareName: REFMAC / Version: 5.8.0107 / Classification: refinement
RefinementResolution: 2.6→71.57 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.904 / SU B: 11.222 / SU ML: 0.136 / Cross valid method: THROUGHOUT / ESU R: 0.236 / ESU R Free: 0.205 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.23234 473 5.3 %RANDOM
Rwork0.19979 ---
obs0.20144 8443 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 45.118 Å2
Baniso -1Baniso -2Baniso -3
1-0.66 Å2-0 Å2-0 Å2
2--0.66 Å2-0 Å2
3----1.32 Å2
Refinement stepCycle: 1 / Resolution: 2.6→71.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms866 0 13 56 935
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.019907
X-RAY DIFFRACTIONr_bond_other_d0.0090.02713
X-RAY DIFFRACTIONr_angle_refined_deg1.4191.9241230
X-RAY DIFFRACTIONr_angle_other_deg0.1881.07232
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3195105
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.85524.25547
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.62215148
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.281154
X-RAY DIFFRACTIONr_chiral_restr0.1180.2118
X-RAY DIFFRACTIONr_gen_planes_refined00.021718
X-RAY DIFFRACTIONr_gen_planes_other00.0132
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_it2.5286.381423
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.3937.12481
X-RAY DIFFRACTIONr_scbond_other4.3887.121482
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined11.43414.956304
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: 2.598→2.666 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.252 35 -
Rwork0.291 612 -
obs--99.39 %
Refinement TLS params.Method: refined / Origin x: -17.3482 Å / Origin y: -28.767 Å / Origin z: -4.0275 Å
111213212223313233
T0.0419 Å2-0.0181 Å20.0093 Å2-0.0809 Å2-0.0296 Å2--0.0129 Å2
L6.7377 °2-0.8019 °21.0612 °2-2.7624 °2-0.6141 °2--3.5585 °2
S0.1032 Å °-0.3739 Å °0.0479 Å °0.3117 Å °-0.0476 Å °0.0561 Å °-0.0985 Å °-0.002 Å °-0.0556 Å °

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