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- PDB-4wvu: CRYSTAL STRUCTURE OF XIAP-BIR2 DOMAIN COMPLEXED WITH LIGAND BOUND -

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Basic information

Entry
Database: PDB / ID: 4wvu
TitleCRYSTAL STRUCTURE OF XIAP-BIR2 DOMAIN COMPLEXED WITH LIGAND BOUND
Components
  • 3,11-DIFLUORO-6,8,13-TRIMETHYL-8H-QUINO[4,3,2-KL]ACRIDIN-13-IUM
  • E3 ubiquitin-protein ligase XIAP
KeywordsAPOPTOSIS / IAP / XIAP-BIR2
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
(3,11-DIFLUORO-6,8,13-TRIMETHYL-8H-QUINO[4,3,2-KL]ACRIDIN-13-IUM / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.02 Å
AuthorsPokross, M.E.
CitationJournal: J.Med.Chem. / Year: 2015
Title: The Discovery of Macrocyclic XIAP Antagonists from a DNA-Programmed Chemistry Library, and Their Optimization To Give Lead Compounds with in Vivo Antitumor Activity.
Authors: Seigal, B.A. / Connors, W.H. / Fraley, A. / Borzilleri, R.M. / Carter, P.H. / Emanuel, S.L. / Fargnoli, J. / Kim, K. / Lei, M. / Naglich, J.G. / Pokross, M.E. / Posy, S.L. / Shen, H. / ...Authors: Seigal, B.A. / Connors, W.H. / Fraley, A. / Borzilleri, R.M. / Carter, P.H. / Emanuel, S.L. / Fargnoli, J. / Kim, K. / Lei, M. / Naglich, J.G. / Pokross, M.E. / Posy, S.L. / Shen, H. / Surti, N. / Talbott, R. / Zhang, Y. / Terrett, N.K.
History
DepositionNov 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2015Group: Database references
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Other / Source and taxonomy
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_entity_src_syn / pdbx_struct_oper_list / struct_conn / struct_conn_type
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_label_atom_id / _citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_entity_src_syn.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_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_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase XIAP
B: 3,11-DIFLUORO-6,8,13-TRIMETHYL-8H-QUINO[4,3,2-KL]ACRIDIN-13-IUM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,3615
Polymers12,1072
Non-polymers2543
Water1,44180
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1270 Å2
ΔGint-14 kcal/mol
Surface area4820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)28.261, 39.328, 33.058
Angle α, β, γ (deg.)90.00, 95.51, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein E3 ubiquitin-protein ligase XIAP / Baculoviral IAP repeat-containing protein 4 / IAP-like protein / hILP / Inhibitor of apoptosis ...Baculoviral IAP repeat-containing protein 4 / IAP-like protein / hILP / Inhibitor of apoptosis protein 3 / hIAP3 / X-linked inhibitor of apoptosis protein / X-linked IAP


Mass: 11359.649 Da / Num. of mol.: 1 / Mutation: C202A, C213G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: XIAP, API3, BIRC4, IAP3 / Plasmid: pET28 / Production host: Escherichia coli (E. coli)
References: UniProt: P98170, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Protein/peptide 3,11-DIFLUORO-6,8,13-TRIMETHYL-8H-QUINO[4,3,2-KL]ACRIDIN-13-IUM


Type: Cyclic peptide / Class: AntagonistReceptor antagonist / Mass: 747.841 Da / Num. of mol.: 1 / Source method: obtained synthetically
References: (3,11-DIFLUORO-6,8,13-TRIMETHYL-8H-QUINO[4,3,2-KL]ACRIDIN-13-IUM

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Non-polymers , 4 types, 83 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 80 / 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: 1.73 Å3/Da / Density % sol: 28.97 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: .98 M AMMONIUM SULFATE and .1 M AMMONIUM FORMATE. Grew single crystals after streak seeding.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Oct 18, 2010
RadiationMonochromator: MicroMax / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.02→39.33 Å / Num. obs: 4708 / % possible obs: 97.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 12.95 Å2 / Rsym value: 0.046 / Net I/σ(I): 18.9
Reflection shellResolution: 2.02→2.13 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.128 / Mean I/σ(I) obs: 8.6 / Rsym value: 0.025 / % possible all: 84

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Processing

Software
NameVersionClassification
XDSdata reduction
SCALAdata scaling
BUSTER2.11.5refinement
PHASERphasing
RefinementResolution: 2.02→25.24 Å / Cor.coef. Fo:Fc: 0.9511 / Cor.coef. Fo:Fc free: 0.9275 / SU R Cruickshank DPI: 0.214 / Cross valid method: FREE R-VALUE / σ(F): 0 / SU R Blow DPI: 0.223 / SU Rfree Blow DPI: 0.151 / SU Rfree Cruickshank DPI: 0.147
RfactorNum. reflection% reflectionSelection details
Rfree0.1781 220 4.7 %RANDOM
Rwork0.1392 ---
obs0.1411 4685 97.22 %-
Displacement parametersBiso mean: 11.15 Å2
Baniso -1Baniso -2Baniso -3
1--0.4682 Å20 Å2-0.3608 Å2
2---0.5547 Å20 Å2
3---1.0229 Å2
Refine analyzeLuzzati coordinate error obs: 0.155 Å
Refinement stepCycle: LAST / Resolution: 2.02→25.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms633 0 65 80 778
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.01776HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.871101HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d255SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes15HARMONIC2
X-RAY DIFFRACTIONt_gen_planes143HARMONIC5
X-RAY DIFFRACTIONt_it776HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.29
X-RAY DIFFRACTIONt_other_torsion14.97
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion81SEMIHARMONIC5
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_contact930SEMIHARMONIC4
LS refinement shellResolution: 2.02→2.26 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.1555 58 4.75 %
Rwork0.1167 1164 -
all0.1187 1222 -
obs--97.22 %
Refinement TLS params.Method: refined / Origin x: 0.6409 Å / Origin y: 4.3663 Å / Origin z: 6.1486 Å
111213212223313233
T-0.0787 Å20.0018 Å20.0049 Å2--0.1035 Å2-0.001 Å2---0.0932 Å2
L0.6978 °2-0.1685 °20.005 °2-1.0069 °2-0.5641 °2--1.1158 °2
S-0.039 Å °-0.0279 Å °0.0128 Å °0.0843 Å °0.0215 Å °-0.0469 Å °-0.0141 Å °0.0473 Å °0.0175 Å °
Refinement TLS groupSelection details: { A|* }

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