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- PDB-4hy0: Crystal structure of XIAP BIR3 with T3256336 -

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Basic information

Entry
Database: PDB / ID: 4hy0
TitleCrystal structure of XIAP BIR3 with T3256336
ComponentsE3 ubiquitin-protein ligase XIAP
KeywordsLIGASE/LIGASE INHIBITOR / BIR3 / Baculoviral IAP repeat-containing protein 4 / Apoptotic suppressor. Inhibitor of caspase-3 / -7 and -9. / Interacts with SMAC and with PRSS25 / XIAP / BIRC4 / X-linked inhibitor of apoptosis / LIGASE-LIGASE INHIBITOR complex
Function / homology
Function and homology information


endopeptidase regulator activity / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / copper ion homeostasis / nucleotide-binding oligomerization domain containing 1 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / protein serine/threonine kinase binding / nucleotide-binding oligomerization domain containing 2 signaling pathway ...endopeptidase regulator activity / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / copper ion homeostasis / nucleotide-binding oligomerization domain containing 1 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / protein serine/threonine kinase binding / nucleotide-binding oligomerization domain containing 2 signaling pathway / SMAC, XIAP-regulated apoptotic response / Regulation of the apoptosome activity / Activation of caspases through apoptosome-mediated cleavage / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / TNFR1-induced proapoptotic signaling / regulation of innate immune response / RIPK1-mediated regulated necrosis / cysteine-type endopeptidase inhibitor activity / protein K63-linked ubiquitination / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / positive regulation of type I interferon production / negative regulation of tumor necrosis factor-mediated signaling pathway / Regulation of PTEN localization / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of protein ubiquitination / Deactivation of the beta-catenin transactivating complex / Regulation of TNFR1 signaling / positive regulation of JNK cascade / RING-type E3 ubiquitin transferase / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / Regulation of necroptotic cell death / Wnt signaling pathway / Regulation of PTEN stability and activity / ubiquitin-protein transferase activity / positive regulation of canonical Wnt signaling pathway / ubiquitin protein ligase activity / regulation of cell population proliferation / regulation of inflammatory response / neuron apoptotic process / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / regulation of cell cycle / defense response to bacterium / DNA damage response / negative regulation of apoptotic process / nucleoplasm / identical protein binding / metal ion 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. / Baculoviral inhibition of apoptosis protein repeat ...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
(3S,7R,8AR)-2-{(2S)-2-(4,4-DIFLUOROCYCLOHEXYL)-2-[(N-METHYL-L-ALANYL)AMINO]ACETYL}-N-[(4R)-3,4-DIHYDRO-2H-CHROMEN-4-YL]-7-ETHOXYOCTAHYDROPYRROLO[1,2-A]PYRAZINE-3-CARBOXAMIDE / Chem-1AQ / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.84 Å
AuthorsSnell, G.S. / Dougan, D.R.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic.
Authors: Hashimoto, K. / Saito, B. / Miyamoto, N. / Oguro, Y. / Tomita, D. / Shiokawa, Z. / Asano, M. / Kakei, H. / Taya, N. / Kawasaki, M. / Sumi, H. / Yabuki, M. / Iwai, K. / Yoshida, S. / ...Authors: Hashimoto, K. / Saito, B. / Miyamoto, N. / Oguro, Y. / Tomita, D. / Shiokawa, Z. / Asano, M. / Kakei, H. / Taya, N. / Kawasaki, M. / Sumi, H. / Yabuki, M. / Iwai, K. / Yoshida, S. / Yoshimatsu, M. / Aoyama, K. / Kosugi, Y. / Kojima, T. / Morishita, N. / Dougan, D.R. / Snell, G.P. / Imamura, S. / Ishikawa, T.
History
DepositionNov 12, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 30, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: Database references
Revision 1.2Aug 7, 2013Group: Non-polymer description / Structure summary
Revision 1.3Feb 28, 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_asym_id / _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_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_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_asym_id / _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_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase XIAP
B: E3 ubiquitin-protein ligase XIAP
C: E3 ubiquitin-protein ligase XIAP
D: E3 ubiquitin-protein ligase XIAP
E: E3 ubiquitin-protein ligase XIAP
F: E3 ubiquitin-protein ligase XIAP
G: E3 ubiquitin-protein ligase XIAP
H: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,42330
Polymers113,6628
Non-polymers5,76122
Water59433
1
A: E3 ubiquitin-protein ligase XIAP
B: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,8888
Polymers28,4152
Non-polymers1,4736
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2230 Å2
ΔGint-84 kcal/mol
Surface area10300 Å2
MethodPISA
2
C: E3 ubiquitin-protein ligase XIAP
H: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,7586
Polymers28,4152
Non-polymers1,3424
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-3 kcal/mol
Surface area10400 Å2
MethodPISA
3
D: E3 ubiquitin-protein ligase XIAP
E: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,8888
Polymers28,4152
Non-polymers1,4736
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2190 Å2
ΔGint-83 kcal/mol
Surface area10440 Å2
MethodPISA
4
F: E3 ubiquitin-protein ligase XIAP
G: E3 ubiquitin-protein ligase XIAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,8888
Polymers28,4152
Non-polymers1,4736
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2210 Å2
ΔGint-84 kcal/mol
Surface area10410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.336, 100.840, 184.583
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
E3 ubiquitin-protein ligase XIAP / Baculoviral IAP repeat-containing protein 4 / IAP-like protein / ILP / hILP / Inhibitor of ...Baculoviral IAP repeat-containing protein 4 / IAP-like protein / ILP / hILP / Inhibitor of apoptosis protein 3 / IAP-3 / hIAP-3 / hIAP3 / X-linked inhibitor of apoptosis protein / X-linked IAP


Mass: 14207.711 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: API3, BIRC4, IAP3, XIAP / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P98170, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-1AQ / (3S,7R,8aR)-2-{(2S)-2-(4,4-difluorocyclohexyl)-2-[(N-methyl-L-alanyl)amino]acetyl}-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-7-ethoxyoctahydropyrrolo[1,2-a]pyrazine-3-carboxamide


Type: Peptide-like / Class: AntagonistReceptor antagonist / Mass: 605.716 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C31H45F2N5O5
References: (3S,7R,8AR)-2-{(2S)-2-(4,4-DIFLUOROCYCLOHEXYL)-2-[(N-METHYL-L-ALANYL)AMINO]ACETYL}-N-[(4R)-3,4-DIHYDRO-2H-CHROMEN-4-YL]-7-ETHOXYOCTAHYDROPYRROLO[1,2-A]PYRAZINE-3-CARBOXAMIDE
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 33 / 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: 2.39 Å3/Da / Density % sol: 48.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.6
Details: 18.5% PEG 4000, 0.08M Tris_base, 0.02M Tris Cl, pH 7.6, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.975 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 19, 2010
RadiationMonochromator: Single Si(220) crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.975 Å / Relative weight: 1
ReflectionResolution: 2.84→50 Å / Num. all: 25173 / Num. obs: 24921 / % possible obs: 99 % / Observed criterion σ(I): -3 / Redundancy: 6.6 % / Net I/σ(I): 20.8
Reflection shellResolution: 2.84→2.9 Å / % possible all: 98.8

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Processing

Software
NameVersionClassification
ALS-BOSdata collection
PHASERphasing
REFMAC5.6.0117refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.84→40 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.929 / SU B: 26.381 / SU ML: 0.3 / Cross valid method: THROUGHOUT / ESU R Free: 0.394 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26221 1331 5.1 %RANDOM
Rwork0.20841 ---
obs0.21111 24921 98.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 74.622 Å2
Baniso -1Baniso -2Baniso -3
1-4.18 Å2-0 Å20 Å2
2--1.42 Å20 Å2
3----5.6 Å2
Refinement stepCycle: LAST / Resolution: 2.84→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6311 0 358 33 6702
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.026895
X-RAY DIFFRACTIONr_bond_other_d0.0010.024498
X-RAY DIFFRACTIONr_angle_refined_deg1.1381.9869380
X-RAY DIFFRACTIONr_angle_other_deg0.821310921
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2265765
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.13324.336339
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.142151040
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2261524
X-RAY DIFFRACTIONr_chiral_restr0.0650.2917
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217511
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021429
LS refinement shellResolution: 2.84→2.913 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.415 99 -
Rwork0.284 1646 -
obs--97.65 %
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)
15.29771.27381.83916.32820.38756.27830.11150.2321-0.4299-0.16530.192-0.7452-0.00720.4852-0.30350.0601-0.06220.00920.2512-0.10840.196-2.129912.205-34.2807
27.93550.03041.74675.36491.5667.97620.09760.9106-0.1261-0.15-0.23921.0038-0.3901-1.39670.14160.1781-0.0411-0.10650.7769-0.06210.295-28.021912.695-41.322
33.84630.62670.25957.05763.58867.91260.1455-0.29980.4216-0.214-0.0531-0.2091-0.5019-0.081-0.09240.25620.12480.09880.17310.09940.2697-20.767411.305713.8219
45.60692.73540.67768.75491.61358.79330.6094-0.28320.13570.7727-0.3314-0.4652-0.44060.5424-0.2780.3601-0.17690.05560.21690.02020.1894-11.304416.8891-9.8686
57.16493.17460.526310.0589-0.25628.2387-0.34680.1705-0.1121-1.0090.77251.19491.0642-1.0139-0.42570.3842-0.2955-0.19090.29140.21910.3052-29.458-0.3346-19.0396
67.3418-2.28870.27547.4434-1.920410.2224-0.236-0.7833-0.04070.83530.1923-0.83850.30941.33220.04360.34030.1391-0.16180.5022-0.180.2612-0.69720.0622-56.6949
74.5714-0.15740.56587.002-1.25029.55290.3369-0.12290.5602-0.6906-0.28510.5776-1.1639-0.7949-0.05180.78120.2375-0.0350.2685-0.19670.3409-18.60417.7417-65.7072
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A254 - 349
2X-RAY DIFFRACTION2B254 - 349
3X-RAY DIFFRACTION3C254 - 350
4X-RAY DIFFRACTION4D254 - 351
5X-RAY DIFFRACTION5E254 - 349
6X-RAY DIFFRACTION6F254 - 349
7X-RAY DIFFRACTION7G254 - 351

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