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- PDB-4wvs: Crystal structure of XIAP-BIR2 domain complexed with (S)-3-(4-met... -

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Basic information

Entry
Database: PDB / ID: 4wvs
TitleCrystal structure of XIAP-BIR2 domain complexed with (S)-3-(4-methoxyphenyl)-2-((S)-2-((S)-1-((S)-2-((S)-2-(methylamino)propanamido)pent-4-ynoyl)pyrrolidine-2-carboxamido)-3-phenylpropanamido)propanoic acid
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 / inhibition of cysteine-type endopeptidase activity / regulation of apoptosis involved in tissue homeostasis / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / copper ion homeostasis / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / nucleotide-binding oligomerization domain containing 1 signaling pathway / nucleotide-binding oligomerization domain containing 2 signaling pathway / SMAC, XIAP-regulated apoptotic response ...endopeptidase regulator activity / inhibition of cysteine-type endopeptidase activity / regulation of apoptosis involved in tissue homeostasis / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / copper ion homeostasis / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / nucleotide-binding oligomerization domain containing 1 signaling pathway / nucleotide-binding oligomerization domain containing 2 signaling pathway / SMAC, XIAP-regulated apoptotic response / Activation of caspases through apoptosome-mediated cleavage / Regulation of the apoptosome activity / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / cysteine-type endopeptidase inhibitor activity / regulation of innate immune response / protein K63-linked ubiquitination / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / negative regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of type I interferon production / protein serine/threonine kinase binding / Regulation of PTEN localization / : / positive regulation of protein ubiquitination / TNFR1-induced NF-kappa-B signaling pathway / Deactivation of the beta-catenin transactivating complex / positive regulation of JNK cascade / Regulation of TNFR1 signaling / RING-type E3 ubiquitin transferase / Regulation of necroptotic cell death / Wnt signaling pathway / Regulation of PTEN stability and activity / ubiquitin-protein transferase activity / ubiquitin protein ligase activity / positive regulation of canonical Wnt signaling pathway / regulation of cell population proliferation / regulation of inflammatory response / regulation of apoptotic process / neuron 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 / nucleus / metal ion binding / 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. ...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
E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.09 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 1.0May 6, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Derived calculations / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_entity_src_syn ...entity_src_gen / pdbx_entity_src_syn / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_entity_src_syn.pdbx_alt_source_flag ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_entity_src_syn.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation / _software.name
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp_atom / chem_comp_bond / database_2 / struct_conn / struct_conn_type
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)12,4817
Polymers12,0352
Non-polymers4465
Water59433
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1590 Å2
ΔGint-44 kcal/mol
Surface area4990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)28.187, 39.269, 32.947
Angle α, β, γ (deg.)90.00, 94.53, 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 / Fragment: UNP residues 156-231 / 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) / Strain (production host): BL21(DE3)
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


Mass: 675.755 Da / Num. of mol.: 1 / Source method: obtained synthetically

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Non-polymers , 4 types, 38 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


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


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / 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: 1.68 Å3/Da / Density % sol: 29.01 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: Crystals were grown in 0.98 M Ammonium Sulfate and 0.1 M Ammonium Formate. Single crystals grew 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: Aug 10, 2010
RadiationMonochromator: MicroMax / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.96→28.1 Å / Num. obs: 4272 / Biso Wilson estimate: 22.62 Å2
Reflection shellResolution: 1.96→1.99 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.177 / Mean I/σ(I) obs: 9.3 / Rsym value: 0 / % possible all: 75.2

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09→28.1 Å / Cor.coef. Fo:Fc: 0.9411 / Cor.coef. Fo:Fc free: 0.9319 / SU R Cruickshank DPI: 0.283 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.27 / SU Rfree Blow DPI: 0.202 / SU Rfree Cruickshank DPI: 0.202
RfactorNum. reflection% reflectionSelection details
Rfree0.2316 230 5.38 %RANDOM
Rwork0.1636 ---
obs0.1674 4272 98.37 %-
Displacement parametersBiso mean: 21.88 Å2
Baniso -1Baniso -2Baniso -3
1--1.3685 Å20 Å2-2.9281 Å2
2--0.6699 Å20 Å2
3---0.6986 Å2
Refine analyzeLuzzati coordinate error obs: 0.187 Å
Refinement stepCycle: LAST / Resolution: 2.09→28.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms642 0 71 33 746
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.01782HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.911100HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d260SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes16HARMONIC2
X-RAY DIFFRACTIONt_gen_planes138HARMONIC5
X-RAY DIFFRACTIONt_it782HARMONIC20
X-RAY DIFFRACTIONt_nbd5SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.35
X-RAY DIFFRACTIONt_other_torsion15.03
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion80SEMIHARMONIC5
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_contact902SEMIHARMONIC4
LS refinement shellResolution: 2.09→2.34 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2057 67 5.75 %
Rwork0.1264 1098 -
all0.1309 1165 -
obs--98.37 %
Refinement TLS params.Method: refined / Origin x: -1.7695 Å / Origin y: -847.322 Å / Origin z: 10.3596 Å
111213212223313233
T-0.0145 Å2-0.0084 Å2-0.0086 Å2--0.0264 Å20.0025 Å2---0.008 Å2
L0.5619 °2-0.0974 °20.1491 °2-1.1833 °20.4164 °2--1.2478 °2
S-0.0336 Å °0.0529 Å °-0.0026 Å °-0.0956 Å °0.0199 Å °0.0161 Å °-0.0117 Å °-0.0517 Å °0.0137 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|-3 - A|231 B|1 - B|5 A|501 - A|501 }A-3 - 231
2X-RAY DIFFRACTION1{ A|-3 - A|231 B|1 - B|5 A|501 - A|501 }B1 - 5
3X-RAY DIFFRACTION1{ A|-3 - A|231 B|1 - B|5 A|501 - A|501 }A501

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