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- PDB-5m6n: Small Molecule inhibitors of IAP -

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Basic information

Entry
Database: PDB / ID: 5m6n
TitleSmall Molecule inhibitors of IAP
ComponentsBaculoviral IAP repeat-containing protein 2
KeywordsAPOPTOSIS / XIAP / metal-binding / inhibitor / Xiap#1
Function / homology
Function and homology information


negative regulation of ripoptosome assembly involved in necroptotic process / regulation of cysteine-type endopeptidase activity / FBXO family protein binding / regulation of RIG-I signaling pathway / positive regulation of protein K48-linked ubiquitination / regulation of non-canonical NF-kappaB signal transduction / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of necroptotic process / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / positive regulation of protein K63-linked ubiquitination ...negative regulation of ripoptosome assembly involved in necroptotic process / regulation of cysteine-type endopeptidase activity / FBXO family protein binding / regulation of RIG-I signaling pathway / positive regulation of protein K48-linked ubiquitination / regulation of non-canonical NF-kappaB signal transduction / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of necroptotic process / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / positive regulation of protein K63-linked ubiquitination / CD40 receptor complex / XY body / negative regulation of necroptotic process / positive regulation of protein monoubiquitination / regulation of reactive oxygen species metabolic process / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / regulation of toll-like receptor signaling pathway / regulation of innate immune response / Apoptotic cleavage of cellular proteins / regulation of cell differentiation / non-canonical NF-kappaB signal transduction / necroptotic process / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / canonical NF-kappaB signal transduction / response to cAMP / tumor necrosis factor-mediated signaling pathway / TICAM1, RIP1-mediated IKK complex recruitment / IKK complex recruitment mediated by RIP1 / placenta development / TNFR1-induced NF-kappa-B signaling pathway / ubiquitin binding / positive regulation of protein ubiquitination / TNFR2 non-canonical NF-kB pathway / Regulation of TNFR1 signaling / RING-type E3 ubiquitin transferase / NOD1/2 Signaling Pathway / Regulation of necroptotic cell death / cytoplasmic side of plasma membrane / protein polyubiquitination / ubiquitin-protein transferase activity / ubiquitin protein ligase activity / regulation of cell population proliferation / regulation of inflammatory response / protein-folding chaperone binding / transferase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / response to ethanol / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / response to hypoxia / cell surface receptor signaling pathway / regulation of cell cycle / Ub-specific processing proteases / apoptotic process / protein-containing complex binding / negative regulation of apoptotic process / zinc ion binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
BIRC2/BIRC3, 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 / Caspase recruitment domain / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. ...BIRC2/BIRC3, 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 / Caspase recruitment domain / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / 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-7H9 / Baculoviral IAP repeat-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.8 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 1.1Jun 21, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
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: Baculoviral IAP repeat-containing protein 2
B: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,96511
Polymers27,3332
Non-polymers1,6329
Water6,287349
1
A: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4355
Polymers13,6661
Non-polymers7684
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,5316
Polymers13,6661
Non-polymers8645
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)30.745, 70.130, 119.034
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Baculoviral IAP repeat-containing protein 2 / Cellular inhibitor of apoptosis 1 / C-IAP1 / IAP homolog B / Inhibitor of apoptosis protein 2 / ...Cellular inhibitor of apoptosis 1 / C-IAP1 / IAP homolog B / Inhibitor of apoptosis protein 2 / hIAP2 / RING finger protein 48 / TNFR2-TRAF-signaling complex protein 2


Mass: 13666.410 Da / Num. of mol.: 2
Mutation: Deletion 1-266, deletion 364-619, insertion 266 MGSSHHHHHH SSGLVPRGSHM
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC2, API1, MIHB, RNF48 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q13490, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-7H9 / 1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2~{H}-pyrrolo[3,2-b]pyridin-1-yl]-2-[(2~{R},5~{R})-5-methyl-2-[[(3~{R})-3-methylmorpholin-4-yl]methyl]piperazin-4-ium-1-yl]ethanone


Mass: 510.667 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H41FN5O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 349 / 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: 2.35 Å3/Da / Density % sol: 47.6 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: .65M (NH4)2SO4 10% Glycerol .4M Li2SO4 .005M TCEP .1M pH=5.6 Na3 citrate/HCl

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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 RAXIS HTC / Detector: IMAGE PLATE / Date: Feb 21, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.691→26.275 Å / Num. obs: 24908 / % possible obs: 87.8 % / Redundancy: 2.5 % / Biso Wilson estimate: 27.07 Å2 / Rmerge(I) obs: 0.033 / Net I/σ(I): 17.7
Reflection shellResolution: 1.8→1.89 Å / Rmerge(I) obs: 0.198 / Mean I/σ(I) obs: 4 / % possible all: 48.5

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.8→23.12 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.93 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.123 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.146 / SU Rfree Blow DPI: 0.129 / SU Rfree Cruickshank DPI: 0.117
RfactorNum. reflection% reflectionSelection details
Rfree0.203 1124 5.16 %RANDOM
Rwork0.166 ---
obs0.168 21769 88.1 %-
Displacement parametersBiso mean: 32.137 Å2
Baniso -1Baniso -2Baniso -3
1-2.5654 Å20 Å20 Å2
2---0.5029 Å20 Å2
3----2.0625 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: 1 / Resolution: 1.8→23.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1576 0 101 349 2026
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0131858HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.952612HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d627SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes40HARMONIC2
X-RAY DIFFRACTIONt_gen_planes267HARMONIC16
X-RAY DIFFRACTIONt_it1858HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion4.91
X-RAY DIFFRACTIONt_other_torsion14.95
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion198SEMIHARMONIC5
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_contact2467SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.89 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.194 -4.87 %
Rwork0.199 1407 -
all0.199 1479 -
obs--46.13 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.0172-0.05930.05290.88840.22320.3778-0.00890.06350.0267-0.0928-0.04860.0397-0.0092-0.03720.0575-0.051-0.0022-0.00560.0164-0.0376-0.018-12.6786-4.45212.56
20.8933-1.27140.83042.3129-1.82231.9856-0.1611-0.0870.11420.1990.0531-0.0751-0.2129-0.03650.108-0.0598-0.0019-0.0291-0.01010.0071-0.0367-0.767-16.713235.2853
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|258 - A|1001 }
2X-RAY DIFFRACTION2{ B|260 - B|1001 }

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