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- PDB-2i3h: Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW) -

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Basic information

Entry
Database: PDB / ID: 2i3h
TitleStructure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)
Components
  • AVPW peptide
  • Baculoviral IAP repeat-containing protein 7
KeywordsINHIBITOR/APOPTOSIS / ZINC BINDING / PEPTIDE COMPLEX / APOPTOSIS INHIBITION / PEPTIDOMIMETIC / SMALL MOLECULE / DRUG DESIGN / INHIBITOR-APOPTOSIS COMPLEX
Function / homology
Function and homology information


regulation of natural killer cell apoptotic process / negative regulation of necroptotic 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 ...regulation of natural killer cell apoptotic process / negative regulation of necroptotic 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 / regulation of cell cycle / protein ubiquitination / centrosome / apoptotic process / negative regulation of apoptotic process / Golgi apparatus / enzyme binding / nucleoplasm / nucleus / metal ion binding / 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 / 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
: / Baculoviral IAP repeat-containing protein 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.62 Å
AuthorsFairbrother, W.J. / Franklin, M.C.
Citation
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.
#1: 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.
#2: 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
DepositionAug 18, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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_atom_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_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 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model
Remark 999SEQUENCE For entity 1 (chains A and B) residues 150, 160-168, and 172 replaced with XIAP-BIR3 homologues.

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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 7
B: Baculoviral IAP repeat-containing protein 7
C: AVPW peptide
D: AVPW peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,36910
Polymers30,8984
Non-polymers4716
Water4,197233
1
A: Baculoviral IAP repeat-containing protein 7
C: AVPW peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5153
Polymers15,4492
Non-polymers651
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area780 Å2
ΔGint-4 kcal/mol
Surface area5590 Å2
MethodPISA
2
B: Baculoviral IAP repeat-containing protein 7
D: AVPW peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,8557
Polymers15,4492
Non-polymers4065
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1070 Å2
ΔGint-9 kcal/mol
Surface area6080 Å2
MethodPISA
3
A: Baculoviral IAP repeat-containing protein 7
B: Baculoviral IAP repeat-containing protein 7
C: AVPW peptide
D: AVPW peptide
hetero molecules

A: Baculoviral IAP repeat-containing protein 7
B: Baculoviral IAP repeat-containing protein 7
C: AVPW peptide
D: AVPW peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,73920
Polymers61,7968
Non-polymers94212
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area8380 Å2
ΔGint-51 kcal/mol
Surface area18670 Å2
MethodPISA
4
B: Baculoviral IAP repeat-containing protein 7
D: AVPW peptide
hetero molecules

A: Baculoviral IAP repeat-containing protein 7
C: AVPW peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,36910
Polymers30,8984
Non-polymers4716
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area2950 Å2
ΔGint-19 kcal/mol
Surface area10580 Å2
MethodPISA
5
A: Baculoviral IAP repeat-containing protein 7
B: Baculoviral IAP repeat-containing protein 7
D: AVPW peptide
hetero molecules

A: Baculoviral IAP repeat-containing protein 7
B: Baculoviral IAP repeat-containing protein 7
D: AVPW peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,79618
Polymers60,8536
Non-polymers94212
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area6590 Å2
ΔGint-41 kcal/mol
Surface area19050 Å2
MethodPISA
6
A: Baculoviral IAP repeat-containing protein 7
B: Baculoviral IAP repeat-containing protein 7
C: AVPW peptide
hetero molecules

A: Baculoviral IAP repeat-containing protein 7
B: Baculoviral IAP repeat-containing protein 7
C: AVPW peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,79618
Polymers60,8536
Non-polymers94212
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area6870 Å2
ΔGint-42 kcal/mol
Surface area18760 Å2
MethodPISA
7
B: Baculoviral IAP repeat-containing protein 7
hetero molecules

A: Baculoviral IAP repeat-containing protein 7
C: AVPW peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,8989
Polymers30,4273
Non-polymers4716
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area2190 Å2
ΔGint-15 kcal/mol
Surface area10620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.541, 87.541, 73.876
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

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


Mass: 14977.567 Da / Num. of mol.: 2 / Fragment: ML-IAP residues 63-172
Mutation: RESIDUES 150, 160-168, AND 172 REPLACED WITH XIAP-BIR3 HOMOLOGUES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC7 / Plasmid: pET15b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q96CA5
#2: Protein/peptide AVPW peptide


Mass: 471.548 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Chemically synthesized peptide

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Non-polymers , 5 types, 239 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#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.: 233 / 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: 2.29 Å3/Da / Density % sol: 46.26 %
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: APS / Beamline: 19-BM / Wavelength: 1.0332 Å
DetectorType: SBC / Detector: CCD / Date: Aug 15, 2003
RadiationMonochromator: Rosenbaum-Rock double-crystal monochromator: Water cooled; sagitally focusing 2nd crystal, Rosenbaum-Rock vertical focusing mirror
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.62→50 Å / Num. all: 37115 / Num. obs: 32349 / % possible obs: 87.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5.9 % / Biso Wilson estimate: 16 Å2 / Rmerge(I) obs: 0.068 / Net I/σ(I): 20.9
Reflection shellResolution: 1.62→1.68 Å / Redundancy: 0.7 % / Rmerge(I) obs: 0.406 / Mean I/σ(I) obs: 1.7 / Num. unique all: 1397 / % possible all: 38.5

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
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: 1.62→20 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.519 / SU ML: 0.049 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.098 / ESU R Free: 0.075 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17965 1631 5.1 %RANDOM
Rwork0.16093 ---
all0.16185 37021 --
obs0.16185 30666 87.24 %-
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: 9.726 Å2
Baniso -1Baniso -2Baniso -3
1--0.64 Å20 Å20 Å2
2---0.64 Å20 Å2
3---1.28 Å2
Refinement stepCycle: LAST / Resolution: 1.62→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1562 0 25 233 1820
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0211643
X-RAY DIFFRACTIONr_bond_other_d0.0020.021365
X-RAY DIFFRACTIONr_angle_refined_deg1.1321.9242218
X-RAY DIFFRACTIONr_angle_other_deg0.74833180
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5235189
X-RAY DIFFRACTIONr_chiral_restr0.0680.2209
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021820
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02373
X-RAY DIFFRACTIONr_nbd_refined0.2020.2345
X-RAY DIFFRACTIONr_nbd_other0.2340.21497
X-RAY DIFFRACTIONr_nbtor_other0.080.2787
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2010.2149
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0970.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.230.261
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1930.229
X-RAY DIFFRACTIONr_mcbond_it1.4212.5964
X-RAY DIFFRACTIONr_mcangle_it2.17651527
X-RAY DIFFRACTIONr_scbond_it1.8422.5679
X-RAY DIFFRACTIONr_scangle_it2.6795691
X-RAY DIFFRACTIONr_rigid_bond_restr0.86621643
X-RAY DIFFRACTIONr_sphericity_free1.0382233
X-RAY DIFFRACTIONr_sphericity_bonded1.13121574
LS refinement shellResolution: 1.62→1.662 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.307 58
Rwork0.326 876
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)
11.7484-0.391-0.30163.342-0.30561.39360.0480.1506-0.0254-0.254-0.0659-0.04590.0622-0.01480.01790.14630.00510.02190.15930.00760.170685.05168.27622.877
21.02540.0350.35782.2785-0.97441.1599-0.0176-0.09580.01180.18420.00450.0035-0.0581-0.04310.01310.15860.00380.01280.13710.00180.156178.3259.78250.769
3-0.6556-2.1066-5.96246.20832.815718.4355-0.4311.0442-0.79250.06420.12130.7165-0.0593-1.1950.30970.11170.0704-0.01640.1846-0.01910.112679.40261.93715.342
41.77043.831.00348.3622-6.338733.0082-0.0981-0.00750.0150.10350.16350.23180.3048-0.2042-0.06540.0127-0.0204-0.00970.0333-0.00040.396568.64555.24248.774
588.4259-1.1598-24.8594187.706831.7684121.97110.6004-1.0142-1.19773.1746-1.98662.34290.3984-1.50381.38630.3343-0.0020.04350.34760.07220.312570.08749.78258.939
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA78 - 16739 - 128
2X-RAY DIFFRACTION1AE10011
3X-RAY DIFFRACTION2BB78 - 17139 - 132
4X-RAY DIFFRACTION2BF10011
5X-RAY DIFFRACTION3CC1 - 41 - 4
6X-RAY DIFFRACTION4DD1 - 41 - 4
7X-RAY DIFFRACTION5BH4011

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