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- PDB-3uw5: Crystal structure of the BIR domain of MLIAP bound to GDC0152 -

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Basic information

Entry
Database: PDB / ID: 3uw5
TitleCrystal structure of the BIR domain of MLIAP bound to GDC0152
Components
  • Baculoviral IAP repeat-containing protein 7, Baculoviral IAP repeat-containing protein 4
  • GDC-0152
KeywordsApoptosis Inhibitor / BIR domain
Function / homology
Function and homology information


regulation of natural killer cell apoptotic process / 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 / Regulation of MITF-M-dependent genes involved in apoptosis ...regulation of natural killer cell apoptotic process / 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 / Regulation of MITF-M-dependent genes involved in apoptosis / 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 / lens development in camera-type eye / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / cysteine-type endopeptidase inhibitor activity / regulation of innate immune response / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / protein K63-linked ubiquitination / 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 / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / 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 / 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 / neuron apoptotic process / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / regulation of cell cycle / protein ubiquitination / defense response to bacterium / centrosome / DNA damage response / negative regulation of apoptotic process / apoptotic process / Golgi apparatus / enzyme binding / 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) / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Death-like domain superfamily / 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
GDC0152 / E3 ubiquitin-protein ligase XIAP / Baculoviral IAP repeat-containing protein 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 Å
AuthorsMaurer, B. / Hymowitz, S.G.
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

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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, Baculoviral IAP repeat-containing protein 4
B: Baculoviral IAP repeat-containing protein 7, Baculoviral IAP repeat-containing protein 4
Z: GDC-0152
Y: GDC-0152
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,4658
Polymers27,1424
Non-polymers3234
Water3,405189
1
A: Baculoviral IAP repeat-containing protein 7, Baculoviral IAP repeat-containing protein 4
Z: GDC-0152
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,7334
Polymers13,5712
Non-polymers1612
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint-1 kcal/mol
Surface area5050 Å2
MethodPISA
2
B: Baculoviral IAP repeat-containing protein 7, Baculoviral IAP repeat-containing protein 4
Y: GDC-0152
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,7334
Polymers13,5712
Non-polymers1612
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1150 Å2
ΔGint-2 kcal/mol
Surface area5390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.396, 87.396, 73.466
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11B-49-

HOH

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Components

#1: Protein Baculoviral IAP repeat-containing protein 7, Baculoviral IAP repeat-containing protein 4 / Kidney inhibitor of apoptosis protein / KIAP / Livin / Melanoma inhibitor of apoptosis protein / ML- ...Kidney inhibitor of apoptosis protein / KIAP / Livin / Melanoma inhibitor of apoptosis protein / ML-IAP / RING finger protein 50 / 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: 13072.521 Da / Num. of mol.: 2 / Fragment: BIR domain 63-179 / Mutation: S150G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: BIRC7, KIAP, LIVIN, MLIAP, RNF50, UNQ5800/PRO19607/PRO21344, API3, BIRC4, IAP3, XIAP
Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q96CA5, UniProt: P98170
#2: Protein/peptide GDC-0152


Type: Peptide-like / Class: Inhibitor / Mass: 498.640 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Synthetic mimetic / References: GDC0152
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / 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: 2.58 Å3/Da / Density % sol: 52.4 %
Crystal growTemperature: 292 K / Method: vapor diffusion / pH: 6
Details: Protein at 25 mg/mL in 10 mM MES was mixed with peptide (AVPW)n a 1:2 protein/peptide ratio. The MLIAP peptide complex was mixed with crystallization well solution (100 mM Bis ...Details: Protein at 25 mg/mL in 10 mM MES was mixed with peptide (AVPW)n a 1:2 protein/peptide ratio. The MLIAP peptide complex was mixed with crystallization well solution (100 mM Bis tris(hydroxymethyl)aminomethane (tris), pH 6; 200 mM lithium sulfate; 20 25% (w/v) poly(ethylene glycol) 3350) in a ratio of 1 uL of protein complex to 1 uL of well solution, VAPOR DIFFUSION, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 19, 2004
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.71→50 Å / Num. all: 31343 / Num. obs: 31343 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7.9 % / Rsym value: 0.055 / Net I/σ(I): 13.9
Reflection shellResolution: 1.71→1.77 Å / Redundancy: 8 % / Mean I/σ(I) obs: 4 / Num. unique all: 3045 / Rsym value: 0.346 / % possible all: 100

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
REFMAC5.6.0117refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.71→50 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.965 / SU B: 2.274 / SU ML: 0.042 / Cross valid method: THROUGHOUT / ESU R Free: 0.07 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1658 1557 5 %RANDOM
Rwork0.15609 ---
all0.15656 31343 --
obs0.15656 31303 99.8 %-
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: 22.935 Å2
Baniso -1Baniso -2Baniso -3
1--0.74 Å20 Å20 Å2
2---0.74 Å2-0 Å2
3---1.48 Å2
Refinement stepCycle: LAST / Resolution: 1.71→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1539 0 12 189 1740
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.021628
X-RAY DIFFRACTIONr_bond_other_d0.0010.021088
X-RAY DIFFRACTIONr_angle_refined_deg1.1381.982208
X-RAY DIFFRACTIONr_angle_other_deg0.8023.0052604
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7365182
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.24522.91179
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.18215222
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.233159
X-RAY DIFFRACTIONr_chiral_restr0.0690.2205
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211802
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02373
LS refinement shellResolution: 1.71→1.754 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.217 104 -
Rwork0.188 1955 -
obs--99.42 %
Refinement TLS params.Method: refined / Origin x: 81.3186 Å / Origin y: 63.9912 Å / Origin z: 36.1251 Å
111213212223313233
T0.0036 Å20.0021 Å20.0095 Å2-0.0145 Å2-0.0036 Å2--0.0427 Å2
L0.5455 °20.1116 °2-0.3496 °2-1.3694 °2-1.0159 °2--2.1807 °2
S0.0163 Å °0.0517 Å °-0.0181 Å °-0.0214 Å °-0.0142 Å °0.0057 Å °-0.0093 Å °-0.0236 Å °-0.0021 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A78 - 167
2X-RAY DIFFRACTION1B78 - 169

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