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- PDB-3gt9: Structure of an ML-IAP/XIAP chimera bound to a peptidomimetic -

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Basic information

Entry
Database: PDB / ID: 3gt9
TitleStructure of an ML-IAP/XIAP chimera bound to a peptidomimetic
ComponentsBaculoviral IAP repeat-containing 7
KeywordsAPOPTOSIS / ZINC BINDING / PEPTIDE COMPLEX / APOPTOSIS INHIBITION / PEPTIDOMIMETIC / SMALL MOLECULE / DRUG DESIGN / METAL-BINDING
Function / homology
Function and homology information


regulation of natural killer cell apoptotic process / lens development in camera-type eye / cysteine-type endopeptidase inhibitor activity / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / negative regulation of tumor necrosis factor-mediated signaling pathway / 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 natural killer cell apoptotic process / lens development in camera-type eye / cysteine-type endopeptidase inhibitor activity / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / negative regulation of tumor necrosis factor-mediated signaling pathway / 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 / protein ubiquitination / regulation of cell cycle / centrosome / apoptotic process / negative regulation of apoptotic process / Golgi apparatus / enzyme binding / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
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 / Zinc finger RING-type signature. ...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-516 / RING-type E3 ubiquitin transferase / Baculoviral IAP repeat-containing protein 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Difference Fourier / Resolution: 1.7 Å
AuthorsFranklin, M.C. / Fairbrother, W.J. / Cohen, F.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres.
Authors: Cohen, F. / Koehler, M.F. / Bergeron, P. / Elliott, L.O. / Flygare, J.A. / Franklin, M.C. / Gazzard, L. / Keteltas, S.F. / Lau, K. / Ly, C.Q. / Tsui, V. / Fairbrother, W.J.
#1: 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.
#2: Journal: ACS CHEM.BIOL. / Year: 2006
Title: Design, synthesis, and biological activity of a potent SMAC mimetic that sensitizes concer 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.
#3: Journal: BIOCHEM.J. / Year: 2005
Title: Engineering ML-IAP to produce an extrordinarily 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.
#4: 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
DepositionMar 27, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Oct 13, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / 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.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_label_seq_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 1.4Feb 21, 2024Group: 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)31,0956
Polymers29,9552
Non-polymers1,1404
Water5,567309
1
A: Baculoviral IAP repeat-containing 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5483
Polymers14,9781
Non-polymers5702
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Baculoviral IAP repeat-containing 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5483
Polymers14,9781
Non-polymers5702
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.531, 87.531, 73.464
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-183-

HOH

DetailsAUTHORS STATE THAT EACH ASYMMETRIC UNIT CONTAINS TWO BIOLOGICAL ASSEMBLIES OF PROTEIN AND LIGAND

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Components

#1: Protein Baculoviral IAP repeat-containing 7


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 / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q6R308, UniProt: Q96CA5*PLUS
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-516 / N-{(1S)-1-cyclohexyl-2-[(2S)-2-(4-naphthalen-1-yl-1,3-thiazol-2-yl)pyrrolidin-1-yl]-2-oxoethyl}-N~2~-methyl-L-alaninamide


Mass: 504.687 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H36N4O2S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 309 / 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: 47.63 %
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: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 15, 2003
RadiationMonochromator: Osmic Blue / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.7→14.86 Å / Num. all: 32040 / Num. obs: 32004 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 11.1 % / Rmerge(I) obs: 0.054 / Net I/σ(I): 41.7
Reflection shellResolution: 1.7→1.76 Å / Redundancy: 9.8 % / Rmerge(I) obs: 0.658 / Mean I/σ(I) obs: 3.9 / Num. unique all: 3164 / % possible all: 99.8

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Processing

Software
NameVersionClassification
MAR345345data collection
REFMAC5.2.0019refinement
DENZOdata reduction
SCALEPACKdata 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: 1.7→14.86 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.957 / SU B: 2.982 / SU ML: 0.049 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.083 / ESU R Free: 0.082 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19337 1594 5 %RANDOM
Rwork0.17021 ---
all0.17 30386 --
obs0.17133 30301 99.72 %-
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: 28.094 Å2
Baniso -1Baniso -2Baniso -3
1--0.54 Å20 Å20 Å2
2---0.54 Å20 Å2
3---1.08 Å2
Refinement stepCycle: LAST / Resolution: 1.7→14.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1446 0 74 309 1829
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0221590
X-RAY DIFFRACTIONr_bond_other_d0.0010.021115
X-RAY DIFFRACTIONr_angle_refined_deg1.0651.9822156
X-RAY DIFFRACTIONr_angle_other_deg0.7623.0052666
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.3525176
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.52623.02676
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.18615216
X-RAY DIFFRACTIONr_dihedral_angle_4_deg8.151158
X-RAY DIFFRACTIONr_chiral_restr0.0540.2200
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021758
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02372
X-RAY DIFFRACTIONr_nbd_refined0.1970.2334
X-RAY DIFFRACTIONr_nbd_other0.1780.21145
X-RAY DIFFRACTIONr_nbtor_refined0.190.2777
X-RAY DIFFRACTIONr_nbtor_other0.0810.2668
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0770.2207
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0870.210
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1470.250
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0890.236
X-RAY DIFFRACTIONr_mcbond_it1.5252.51145
X-RAY DIFFRACTIONr_mcbond_other0.2332.5361
X-RAY DIFFRACTIONr_mcangle_it1.76151409
X-RAY DIFFRACTIONr_scbond_it1.4382.5894
X-RAY DIFFRACTIONr_scangle_it2.3285747
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.268 132 -
Rwork0.258 2187 -
obs--99.83 %
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)
12.3505-1.4031-0.41784.19830.00452.28640.1160.2353-0.0817-0.3413-0.13890.03250.0471-0.05770.0229-0.21940.0120.0177-0.19940.007-0.218184.640568.055821.805
21.0006-0.32750.14853.4533-1.81332.45630.0041-0.0798-0.00070.22590.0350.1289-0.0784-0.0745-0.0391-0.2261-0.00350.0291-0.22940.0031-0.219877.848359.507249.9607
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A78 - 167
2X-RAY DIFFRACTION1A1001
3X-RAY DIFFRACTION1A1
4X-RAY DIFFRACTION2B78 - 116
5X-RAY DIFFRACTION2B120 - 169
6X-RAY DIFFRACTION2B1001
7X-RAY DIFFRACTION2B1

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