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- PDB-3f7h: Structure of an ML-IAP/XIAP chimera bound to a peptidomimetic -

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Basic information

Entry
Database: PDB / ID: 3f7h
TitleStructure of an ML-IAP/XIAP chimera bound to a peptidomimetic
ComponentsBaculoviral IAP repeat-containing protein 7
KeywordsAPOPTOSIS / ZINC BINDING / PEPTIDE COMPLEX / APOPTOSIS INHIBITION / PEPTIDOMIMETIC / SMALL MOLECULE / DRUG DESIGN / Metal-binding / Nucleus / Zinc-finger
Function / homology
Function and homology information


regulation of natural killer cell apoptotic process / Regulation of MITF-M-dependent genes involved in apoptosis / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / lens development in camera-type eye / negative regulation of tumor necrosis factor-mediated signaling pathway / cysteine-type endopeptidase inhibitor activity / positive regulation of protein ubiquitination / positive regulation of JNK cascade / RING-type E3 ubiquitin transferase / ubiquitin-protein transferase activity ...regulation of natural killer cell apoptotic process / Regulation of MITF-M-dependent genes involved in apoptosis / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / lens development in camera-type eye / negative regulation of tumor necrosis factor-mediated signaling pathway / cysteine-type endopeptidase inhibitor activity / positive regulation of protein ubiquitination / positive regulation of JNK cascade / RING-type E3 ubiquitin transferase / ubiquitin-protein transferase activity / ubiquitin protein ligase activity / regulation of cell population proliferation / regulation of apoptotic process / regulation of cell cycle / protein ubiquitination / apoptotic process / centrosome / negative regulation of apoptotic process / enzyme binding / Golgi apparatus / zinc ion binding / nucleoplasm / metal ion binding / nucleus / cytoplasm / cytosol
Similarity search - Function
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) / Zinc finger, RING-type, conserved site ...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) / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-419 / : / RING-type E3 ubiquitin transferase / Baculoviral IAP repeat-containing protein 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / difference Fourier / Resolution: 1.8 Å
AuthorsFranklin, M.C. / Fairbrother, W.J. / Cohen, F.
Citation
Journal: J.Med.Chem. / Year: 2009
Title: Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold
Authors: Cohen, F. / Alicke, B. / Elliott, L.O. / Flygare, J.A. / Goncharov, T. / Keteltas, S.F. / Franklin, M.C. / Frankovitz, S. / Stephan, J.P. / Tsui, V. / Vucic, D. / Wong, H. / Fairbrother, W.J.
#1: Journal: ACS Chem. Biol. / Year: 2006
Title: Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs.
Authors: Zobel, K. / Wang, L. / Varfolomeev, E. / Franklin, M.C. / Elliott, L.O. / Wallweber, H.J. / Okawa, D.C. / Flygare, J.A. / Vucic, D. / Fairbrother, W.J. / Deshayes, K.
#2: Journal: Biochem. J. / Year: 2005
Title: Engineering ML-IAP to produce an extraordinarily potent caspase-9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP.
Authors: Vucic, D. / Franklin, M.C. / Wallweber, H.J. / Das, K. / Eckelman, B.P. / Shin, H. / Elliott, L.O. / Deshayes, K. / Salvesen, G.S. / Fairbrother, W.J.
#3: Journal: Biochemistry / Year: 2003
Title: Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP)
Authors: Franklin, M.C. / Kadkhodayan, S. / Ackerly, H. / Alexandru, D. / Distefano, M.D. / Elliott, L.O. / Flygare, J.A. / Vucic, D. / Deshayes, K. / Fairbrother, W.J.
History
DepositionNov 9, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 17, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_special_symmetry ...database_2 / pdbx_struct_special_symmetry / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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.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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Dec 27, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.5Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Baculoviral IAP repeat-containing protein 7
B: Baculoviral IAP repeat-containing protein 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,46410
Polymers29,9552
Non-polymers1,5098
Water3,765209
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A: Baculoviral IAP repeat-containing protein 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5623
Polymers14,9781
Non-polymers5842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Baculoviral IAP repeat-containing protein 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,9027
Polymers14,9781
Non-polymers9246
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.048, 88.048, 73.321
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-181-

HOH

21A-189-

HOH

31A-299-

HOH

41B-253-

HOH

DetailsAuthors state that each asymmetric unit contains two biological assemblies of protein and ligand

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Baculoviral IAP repeat-containing protein 7 / Kidney inhibitor of apoptosis protein / KIAP / Melanoma inhibitor of apoptosis protein / ML-IAP / ...Kidney inhibitor of apoptosis protein / KIAP / Melanoma inhibitor of apoptosis protein / ML-IAP / Livin / RING finger protein 50


Mass: 14977.567 Da / Num. of mol.: 2 / Fragment: ML-IAP RESIDUES 63-172
Mutation: S150G; R160Q; D161E; F162Y; V163I; H164N; S165N; V166I; Q167H; E168L; Q172L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: BIRC7, KIAP, LIVIN, MLIAP, RNF50, UNQ5800/PRO19607/PRO21344
Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q6R308, UniProt: Q96CA5*PLUS

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Non-polymers , 6 types, 217 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-419 / N-[(3aR,6S,6aS)-1-(N-methyl-L-alanyl-3-methyl-L-valyl)octahydrocyclopenta[b]pyrrol-6-yl]-2,2-diphenylacetamide


Mass: 518.690 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H42N4O3
#4: Chemical ChemComp-LI / LITHIUM ION


Mass: 6.941 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Li
#5: Chemical ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 2.37 Å3/Da / Density % sol: 48.14 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: LITHIUM SULFATE, PEG 3350, BIS-TRIS, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Mar 8, 2005
RadiationMonochromator: Single crystal, cylindrically bent, Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. all: 27379 / Num. obs: 27289 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7.1 % / Biso Wilson estimate: 23.8 Å2 / Rmerge(I) obs: 0.082 / Rsym value: 0.082 / Net I/σ(I): 24.7
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.457 / Mean I/σ(I) obs: 3.4 / Num. unique all: 2669 / Rsym value: 0.457 / % possible all: 97.4

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Processing

Software
NameVersionClassification
HKL-2000data collection
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: difference Fourier
Starting model: 1.3 A STRUCTURE OF THE ML-IAP/XIAP PROTEIN BOUND TO A DIFFERENT PEPTIDOMIMETIC, WITH THE LIGAND AND SURROUNDING WATERS REMOVED

Resolution: 1.8→25 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.956 / SU B: 3.11 / SU ML: 0.051 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.085 / ESU R Free: 0.084 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17516 1359 5 %RANDOM
Rwork0.14921 ---
all0.15 25926 --
obs0.15048 25848 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 21.335 Å2
Baniso -1Baniso -2Baniso -3
1--0.7 Å20 Å20 Å2
2---0.7 Å20 Å2
3---1.41 Å2
Refinement stepCycle: LAST / Resolution: 1.8→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1479 0 101 209 1789
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0211651
X-RAY DIFFRACTIONr_bond_other_d0.0010.021156
X-RAY DIFFRACTIONr_angle_refined_deg1.1081.9872232
X-RAY DIFFRACTIONr_angle_other_deg0.8423.0042761
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5195181
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.56123.03879
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.35315220
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.559158
X-RAY DIFFRACTIONr_chiral_restr0.0660.2210
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021815
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02388
X-RAY DIFFRACTIONr_nbd_refined0.2010.2334
X-RAY DIFFRACTIONr_nbd_other0.1880.21175
X-RAY DIFFRACTIONr_nbtor_refined0.1860.2790
X-RAY DIFFRACTIONr_nbtor_other0.0810.2686
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1030.2132
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1970.27
X-RAY DIFFRACTIONr_symmetry_vdw_other0.220.234
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1440.226
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.8342.51172
X-RAY DIFFRACTIONr_mcbond_other0.2832.5370
X-RAY DIFFRACTIONr_mcangle_it2.11751446
X-RAY DIFFRACTIONr_scbond_it1.9372.5915
X-RAY DIFFRACTIONr_scangle_it2.8885786
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.211 93 -
Rwork0.183 1823 -
obs--97.01 %
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)
12.0506-1.0483-0.24443.30640.17151.88590.08010.1799-0.0288-0.257-0.0943-0.0137-0.02010.00190.0142-0.17920.00270.0098-0.1461-0.0016-0.176385.395668.877522.1313
21.472-0.43390.39043.2105-1.20211.6620.0075-0.1153-0.03930.19050.00460.0654-0.0561-0.0102-0.0121-0.1726-0.01280.016-0.17660.0005-0.178778.606960.190749.8584
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A78 - 167
2X-RAY DIFFRACTION1A1001
3X-RAY DIFFRACTION2B78 - 170
4X-RAY DIFFRACTION2B1001

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