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- PDB-5m6e: Small Molecule inhibitors of IAP -

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Basic information

Entry
Database: PDB / ID: 5m6e
TitleSmall Molecule inhibitors of IAP
ComponentsE3 ubiquitin-protein ligase XIAP
KeywordsAPOPTOSIS / XIAP / metal-binding / inhibitor / Xiap#1
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
Chem-7HT / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.32 Å
AuthorsWilliams, P.A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP).
Authors: Tamanini, E. / Buck, I.M. / Chessari, G. / Chiarparin, E. / Day, J.E.H. / Frederickson, M. / Griffiths-Jones, C.M. / Hearn, K. / Heightman, T.D. / Iqbal, A. / Johnson, C.N. / Lewis, E.J. / ...Authors: Tamanini, E. / Buck, I.M. / Chessari, G. / Chiarparin, E. / Day, J.E.H. / Frederickson, M. / Griffiths-Jones, C.M. / Hearn, K. / Heightman, T.D. / Iqbal, A. / Johnson, C.N. / Lewis, E.J. / Martins, V. / Peakman, T. / Reader, M. / Rich, S.J. / Ward, G.A. / Williams, P.A. / Wilsher, N.E.
History
DepositionOct 25, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 24, 2017Provider: repository / Type: Initial release
Revision 2.0Jun 28, 2017Group: Database references / Non-polymer description / Structure summary
Category: citation / entity
Item: _chem_comp.formula / _chem_comp.name ..._chem_comp.formula / _chem_comp.name / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _entity.formula_weight / _entity.pdbx_description
Revision 3.0May 8, 2024Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _atom_site.occupancy / _database_2.pdbx_DOI ..._atom_site.occupancy / _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_asym_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_asym_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_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry

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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)15,2155
Polymers14,5751
Non-polymers6404
Water3,729207
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area410 Å2
ΔGint-4 kcal/mol
Surface area6450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.525, 71.525, 105.693
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-402-

NA

21A-532-

HOH

31A-637-

HOH

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Components

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Protein , 1 types, 1 molecules A

#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: 14575.300 Da / Num. of mol.: 1
Mutation: deletion 1-248, deletion 355-497, insertion 240 MGSSHHHHHHSSGLVPRGSH
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: XIAP, API3, BIRC4, IAP3 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P98170, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)

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Non-polymers , 5 types, 211 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-7HT / 1-[3,3-dimethyl-6-(phenylmethyl)-2~{H}-pyrrolo[3,2-c]pyridin-1-yl]-2-[(2~{R},5~{R})-5-methyl-2-[(4-methylpyrazol-1-yl)methyl]piperazin-4-ium-1-yl]ethanone


Mass: 473.633 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H37N6O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 207 / 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: 4.64 Å3/Da / Density % sol: 73.48 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 3.2M NaCl, 0.1M HEPES/NaOHpH=8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54187 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: May 19, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 2.284→28.909 Å / Num. obs: 12468 / % possible obs: 95.6 % / Redundancy: 2.4 % / Rmerge(I) obs: 0.039 / Net I/σ(I): 17.5
Reflection shellResolution: 2.31→2.41 Å / Rmerge(I) obs: 0.207 / Mean I/σ(I) obs: 4.4 / % possible all: 85.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.32→28.909 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.913 / SU B: 8.075 / SU ML: 0.119 / Cross valid method: THROUGHOUT / ESU R: 0.182 / ESU R Free: 0.183 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23923 646 5.4 %RANDOM
Rwork0.18326 ---
obs0.18621 11208 95.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 43.572 Å2
Baniso -1Baniso -2Baniso -3
1--0.09 Å20 Å2-0 Å2
2---0.09 Å2-0 Å2
3---0.18 Å2
Refinement stepCycle: 1 / Resolution: 2.32→28.909 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms860 0 41 207 1108
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.019961
X-RAY DIFFRACTIONr_bond_other_d0.0020.02853
X-RAY DIFFRACTIONr_angle_refined_deg1.4791.9131314
X-RAY DIFFRACTIONr_angle_other_deg1.0072.8991978
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5965114
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.41424.73152
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.15115.19158
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.559153
X-RAY DIFFRACTIONr_chiral_restr0.1040.2124
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.0211105
X-RAY DIFFRACTIONr_gen_planes_other00.02238
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_it2.8485.708433
X-RAY DIFFRACTIONr_mcbond_other2.8465.688432
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.7136.589528
X-RAY DIFFRACTIONr_scbond_other3.7096.59529
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined8.2913.613332
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: 2.319→2.379 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.25 36 -
Rwork0.24 706 -
obs--83.46 %
Refinement TLS params.Method: refined / Origin x: -17.1938 Å / Origin y: -28.9723 Å / Origin z: -4.2808 Å
111213212223313233
T0.0379 Å2-0.0216 Å20.0065 Å2-0.1037 Å2-0.0276 Å2--0.0087 Å2
L6.1948 °2-0.5452 °21.3642 °2-2.9851 °2-0.059 °2--3.1955 °2
S0.0856 Å °-0.2554 Å °0.0102 Å °0.2968 Å °-0.0385 Å °0.0206 Å °-0.0587 Å °-0.0274 Å °-0.0471 Å °

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