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- PDB-3uw4: Crystal structure of cIAP1 BIR3 bound to GDC0152 -

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Basic information

Entry
Database: PDB / ID: 3uw4
TitleCrystal structure of cIAP1 BIR3 bound to GDC0152
Components
  • Baculoviral IAP repeat-containing protein 2, Baculoviral IAP repeat-containing protein 4
  • GDC0152
KeywordsApoptosis Inhibitor / BIR domain
Function / homology
Function and homology information


negative regulation of ripoptosome assembly involved in necroptotic process / regulation of cysteine-type endopeptidase activity / FBXO family protein binding / regulation of RIG-I signaling pathway / positive regulation of protein K48-linked ubiquitination / endopeptidase regulator activity / regulation of non-canonical NF-kappaB signal transduction / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination ...negative regulation of ripoptosome assembly involved in necroptotic process / regulation of cysteine-type endopeptidase activity / FBXO family protein binding / regulation of RIG-I signaling pathway / positive regulation of protein K48-linked ubiquitination / endopeptidase regulator activity / regulation of non-canonical NF-kappaB signal transduction / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of necroptotic process / copper ion homeostasis / nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of protein K63-linked ubiquitination / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / CD40 receptor complex / XY body / protein serine/threonine kinase binding / negative regulation of necroptotic process / 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 / positive regulation of protein monoubiquitination / regulation of reactive oxygen species metabolic process / TNFR1-induced proapoptotic signaling / regulation of innate immune response / RIPK1-mediated regulated necrosis / cysteine-type endopeptidase inhibitor activity / regulation of toll-like receptor signaling pathway / Apoptotic cleavage of cellular proteins / regulation of cell differentiation / protein K63-linked ubiquitination / non-canonical NF-kappaB signal transduction / necroptotic process / 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 / canonical NF-kappaB signal transduction / response to cAMP / tumor necrosis factor-mediated signaling pathway / Regulation of PTEN localization / TICAM1, RIP1-mediated IKK complex recruitment / IKK complex recruitment mediated by RIP1 / placenta development / TNFR1-induced NF-kappa-B signaling pathway / ubiquitin binding / positive regulation of protein ubiquitination / TNFR2 non-canonical NF-kB pathway / Deactivation of the beta-catenin transactivating complex / Regulation of TNFR1 signaling / positive regulation of JNK cascade / RING-type E3 ubiquitin transferase / NOD1/2 Signaling Pathway / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / cytoplasmic side of plasma membrane / Regulation of necroptotic cell death / Wnt signaling pathway / Regulation of PTEN stability and activity / protein polyubiquitination / ubiquitin-protein transferase activity / positive regulation of canonical Wnt signaling pathway / ubiquitin protein ligase activity / regulation of cell population proliferation / regulation of inflammatory response / protein-folding chaperone binding / transferase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / neuron apoptotic process / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / response to ethanol / transcription coactivator activity / response to hypoxia / cell surface receptor signaling pathway / regulation of cell cycle / Ub-specific processing proteases / defense response to bacterium / apoptotic process / DNA damage response / protein-containing complex binding / negative regulation of apoptotic process / zinc ion binding / nucleoplasm / identical protein binding / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
BIRC2/BIRC3, UBA domain / 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 / Caspase recruitment domain / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain ...BIRC2/BIRC3, UBA domain / 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 / Caspase recruitment domain / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / 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
GDC0152 / E3 ubiquitin-protein ligase XIAP / Baculoviral IAP repeat-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsMaurer, B. / Hymowitz, S.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152).
Authors: Flygare, J.A. / Beresini, M. / Budha, N. / Chan, H. / Chan, I.T. / Cheeti, S. / Cohen, F. / Deshayes, K. / Doerner, K. / Eckhardt, S.G. / Elliott, L.O. / Feng, B. / Franklin, M.C. / Reisner, ...Authors: Flygare, J.A. / Beresini, M. / Budha, N. / Chan, H. / Chan, I.T. / Cheeti, S. / Cohen, F. / Deshayes, K. / Doerner, K. / Eckhardt, S.G. / Elliott, L.O. / Feng, B. / Franklin, M.C. / Reisner, S.F. / Gazzard, L. / Halladay, J. / Hymowitz, S.G. / La, H. / Lorusso, P. / Maurer, B. / Murray, L. / Plise, E. / Quan, C. / Stephan, J.P. / Young, S.G. / Tom, J. / Tsui, V. / Um, J. / Varfolomeev, E. / Vucic, D. / Wagner, A.J. / Wallweber, H.J. / Wang, L. / Ware, J. / Wen, Z. / Wong, H. / Wong, J.M. / Wong, M. / Wong, S. / Yu, R. / Zobel, K. / Fairbrother, W.J.
History
DepositionNov 30, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 28, 2012Group: Database references
Revision 1.2May 23, 2012Group: Database references
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Aug 2, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.5Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif
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.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_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.pdbx_leaving_atom_flag / _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_ref_seq_dif.details
Revision 1.6Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Baculoviral IAP repeat-containing protein 2, Baculoviral IAP repeat-containing protein 4
Z: GDC0152
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,2534
Polymers11,1232
Non-polymers1312
Water95553
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1110 Å2
ΔGint-24 kcal/mol
Surface area5190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)35.691, 37.380, 57.598
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 Baculoviral IAP repeat-containing protein 2, Baculoviral IAP repeat-containing protein 4 / C-IAP1 / IAP homolog B / Inhibitor of apoptosis protein 2 / IAP-2 / hIAP-2 / hIAP2 / RING finger ...C-IAP1 / IAP homolog B / Inhibitor of apoptosis protein 2 / IAP-2 / hIAP-2 / hIAP2 / RING finger protein 48 / TNFR2-TRAF-signaling complex protein 2 / E3 ubiquitin-protein ligase XIAP / 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: 10623.998 Da / Num. of mol.: 1 / Fragment: BIR3 residues 266-354 / Mutation: C292S, R332G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: API1, BIRC2, cIAP1, IAP2, MIHB, RNF48, API3, BIRC4, IAP3, XIAP
Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q13490, UniProt: P98170
#2: Protein/peptide GDC0152


Type: Peptide-like / Class: Inhibitor / Mass: 498.640 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Synthetic inhibitor / References: GDC0152
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 53 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 1.81 Å3/Da / Density % sol: 32.4 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.6
Details: Protein Solution (4mg/mL cIAP with 1 mM GDC-0152, 50 mM HEPES pH 7.2, 300 mM NaCl, 0.2 mM TCEP) was mixed with equal volumes of resevoir solution (0.1 M Tris-HCl pH 8.6, 0.5 M Magnesium ...Details: Protein Solution (4mg/mL cIAP with 1 mM GDC-0152, 50 mM HEPES pH 7.2, 300 mM NaCl, 0.2 mM TCEP) was mixed with equal volumes of resevoir solution (0.1 M Tris-HCl pH 8.6, 0.5 M Magnesium Formate)., VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 8, 2008
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.79→50 Å / Num. all: 7548 / Num. obs: 7548 / % possible obs: 98 % / Observed criterion σ(F): -3 / Observed criterion σ(I): 0 / Redundancy: 1.9 % / Rsym value: 0.085 / Net I/σ(I): 10.4
Reflection shellResolution: 1.79→1.85 Å / Redundancy: 1.9 % / Mean I/σ(I) obs: 2.6 / Num. unique all: 734 / Rsym value: 0.467 / % possible all: 99.2

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
REFMAC5.6.0117refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb code 2UVL

2uvl


Resolution: 1.79→31.36 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.94 / SU B: 5.83 / SU ML: 0.091 / Cross valid method: THROUGHOUT / ESU R Free: 0.142 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.22113 736 9.8 %RANDOM
Rwork0.17706 ---
all0.18134 7661 --
obs0.18134 7503 97.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.068 Å2
Baniso -1Baniso -2Baniso -3
1--1.63 Å20 Å20 Å2
2---0.98 Å2-0 Å2
3---2.61 Å2
Refinement stepCycle: LAST / Resolution: 1.79→31.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms746 0 2 53 801
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.02780
X-RAY DIFFRACTIONr_bond_other_d0.0030.023
X-RAY DIFFRACTIONr_angle_refined_deg1.371.9591053
X-RAY DIFFRACTIONr_angle_other_deg1.02339
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.15586
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.19923.07739
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.07215112
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.882155
X-RAY DIFFRACTIONr_chiral_restr0.0890.299
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021618
LS refinement shellResolution: 1.79→1.827 Å / Total num. of bins used: 25
RfactorNum. reflection% reflection
Rfree0.296 40 -
Rwork0.209 325 -
obs--96.82 %
Refinement TLS params.Method: refined / Origin x: -6.7745 Å / Origin y: 2.3651 Å / Origin z: -3.9479 Å
111213212223313233
T0.0282 Å2-0.0062 Å20.0095 Å2-0.0134 Å2-0.0051 Å2--0.009 Å2
L2.2985 °2-0.8087 °20.6958 °2-1.496 °2-0.6166 °2--1.2721 °2
S0.0037 Å °0.0546 Å °0.0889 Å °0.0238 Å °-0.0242 Å °-0.0263 Å °-0.0054 Å °0.0322 Å °0.0205 Å °

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