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- PDB-5tr4: Structure of Ubiquitin activating enzyme (Uba1) in complex with u... -

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Basic information

Entry
Database: PDB / ID: 5tr4
TitleStructure of Ubiquitin activating enzyme (Uba1) in complex with ubiquitin and TAK-243
Components
  • Ubiquitin-activating enzyme E1 1
  • Ubiquitin
KeywordsLIGASE/LIGASE INHIBITOR / LIGASE-LIGASE INHIBITOR complex
Function / homology
Function and homology information


Translation initiation complex formation / Formation of the ternary complex, and subsequently, the 43S complex / Ribosomal scanning and start codon recognition / E1 ubiquitin-activating enzyme / Neddylation / ubiquitin activating enzyme activity / Major pathway of rRNA processing in the nucleolus and cytosol / GTP hydrolysis and joining of the 60S ribosomal subunit / Translesion synthesis by REV1 / Recognition of DNA damage by PCNA-containing replication complex ...Translation initiation complex formation / Formation of the ternary complex, and subsequently, the 43S complex / Ribosomal scanning and start codon recognition / E1 ubiquitin-activating enzyme / Neddylation / ubiquitin activating enzyme activity / Major pathway of rRNA processing in the nucleolus and cytosol / GTP hydrolysis and joining of the 60S ribosomal subunit / Translesion synthesis by REV1 / Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / Downregulation of ERBB4 signaling / Spry regulation of FGF signaling / Downregulation of ERBB2:ERBB3 signaling / NOD1/2 Signaling Pathway / APC/C:Cdc20 mediated degradation of Cyclin B / SCF-beta-TrCP mediated degradation of Emi1 / APC-Cdc20 mediated degradation of Nek2A / EGFR downregulation / TCF dependent signaling in response to WNT / NRIF signals cell death from the nucleus / p75NTR recruits signalling complexes / NF-kB is activated and signals survival / Activated NOTCH1 Transmits Signal to the Nucleus / Downregulation of TGF-beta receptor signaling / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Downregulation of SMAD2/3:SMAD4 transcriptional activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Senescence-Associated Secretory Phenotype (SASP) / Regulation of innate immune responses to cytosolic DNA / activated TAK1 mediates p38 MAPK activation / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Regulation of FZD by ubiquitination / PINK1-PRKN Mediated Mitophagy / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Regulation of TNFR1 signaling / TNFR1-induced NF-kappa-B signaling pathway / Translesion synthesis by POLK / Translesion synthesis by POLI / Regulation of necroptotic cell death / MAP3K8 (TPL2)-dependent MAPK1/3 activation / HDR through Homologous Recombination (HRR) / Josephin domain DUBs / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / DNA Damage Recognition in GG-NER / Formation of Incision Complex in GG-NER / Gap-filling DNA repair synthesis and ligation in GG-NER / Dual Incision in GG-NER / Fanconi Anemia Pathway / Regulation of TP53 Activity through Phosphorylation / Regulation of TP53 Degradation / Regulation of TP53 Activity through Methylation / Negative regulation of MET activity / Cyclin D associated events in G1 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Downregulation of ERBB2 signaling / E3 ubiquitin ligases ubiquitinate target proteins / Regulation of PTEN localization / ER Quality Control Compartment (ERQC) / Regulation of expression of SLITs and ROBOs / Interferon alpha/beta signaling / Endosomal Sorting Complex Required For Transport (ESCRT) / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / IRAK2 mediated activation of TAK1 complex / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Alpha-protein kinase 1 signaling pathway / RAS processing / Pexophagy / Inactivation of CSF3 (G-CSF) signaling / Negative regulation of FLT3 / Regulation of BACH1 activity / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / Regulation of NF-kappa B signaling / Termination of translesion DNA synthesis / Ovarian tumor domain proteases / Negative regulators of DDX58/IFIH1 signaling / Negative regulation of FGFR1 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / Negative regulation of MAPK pathway / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Iron uptake and transport / Deactivation of the beta-catenin transactivating complex / Metalloprotease DUBs / Formation of TC-NER Pre-Incision Complex / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Activation of NF-kappaB in B cells / L13a-mediated translational silencing of Ceruloplasmin expression / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / SRP-dependent cotranslational protein targeting to membrane / SCF(Skp2)-mediated degradation of p27/p21 / FCERI mediated NF-kB activation / Autodegradation of the E3 ubiquitin ligase COP1 / Asymmetric localization of PCP proteins
Similarity search - Function
Ubiquitin-activating enzyme E1, inactive adenylation domain, subdomain 2 / Ubiquitin-activating enzyme E1, inactive adenylation domain, subdomain 1 / Ubiquitin-activating enzyme E1, UFD domain / Ubiquitin-activating enzyme E1, SCCH domain / Ubiquitin-activating enzyme E1, FCCH domain / Ubiquitin-activating enzyme E1, conserved site / Ubiquitin-activating enzyme signature 1. / Ubiquitin-activating enzyme E1 / Ubiquitin-activating enzyme E1, C-terminal / Ubiquitin-activating enzyme E1, FCCH domain ...Ubiquitin-activating enzyme E1, inactive adenylation domain, subdomain 2 / Ubiquitin-activating enzyme E1, inactive adenylation domain, subdomain 1 / Ubiquitin-activating enzyme E1, UFD domain / Ubiquitin-activating enzyme E1, SCCH domain / Ubiquitin-activating enzyme E1, FCCH domain / Ubiquitin-activating enzyme E1, conserved site / Ubiquitin-activating enzyme signature 1. / Ubiquitin-activating enzyme E1 / Ubiquitin-activating enzyme E1, C-terminal / Ubiquitin-activating enzyme E1, FCCH domain / Ubiquitin-activating enzyme E1, four-helix bundle / Ubiquitin-activating enzyme E1, C-terminal domain superfamily / Ubiquitin-activating enzyme E1, SCCH domain / Ubiquitin-activating enzyme E1, FCCH domain superfamily / Ubiquitin fold domain / Ubiquitin-activating enzyme E1 FCCH domain / Ubiquitin-activating enzyme E1 four-helix bundle / Ubiquitin-activating enzyme e1 C-terminal domain / Ubiquitin-activating enzyme, SCCH domain / Ubiquitin-activating enzyme, SCCH domain / Ubiquitin/SUMO-activating enzyme E1-like / Ubiquitin-activating enzyme E1, inactive adenylation domain, subdomain 1 / Ubiquitin-activating enzyme E1, Cys active site / Ubiquitin-activating enzyme active site. / ThiF/MoeB/HesA family / Ubiquitin-activating enzyme / THIF-type NAD/FAD binding fold / ThiF family / Structural Genomics Hypothetical 15.5 Kd Protein In mrcA-pckA Intergenic Region; Chain A / Elongation Factor Tu (Ef-tu); domain 3 / FAD/NAD(P)-binding domain / Ubiquitin conserved site / Ubiquitin domain / 3-Layer(bba) Sandwich / Ubiquitin domain signature. / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Arc Repressor Mutant, subunit A / Ubiquitin-like domain superfamily / NAD(P)-binding Rossmann-like Domain / Roll / Beta Barrel / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-61T / Polyubiquitin-B / Ubiquitin-activating enzyme E1 1
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
Bos taurus (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsSintchak, M.D.
CitationJournal: To be published
Title: Identification and Characterization of a Small Molecule Inhibitor of the Ubiquitin Activating Enzyme (TAK-243)
Authors: Hyer, M. / Milhollen, M. / Ciavarri, J. / Fleming, P. / Traore, T. / Sappal, D. / Huck, J. / Shi, J. / Gavin, J. / Brownell, J. / Yang, Y. / Stringer, B. / Griffin, R. / Bruzzese, F. / ...Authors: Hyer, M. / Milhollen, M. / Ciavarri, J. / Fleming, P. / Traore, T. / Sappal, D. / Huck, J. / Shi, J. / Gavin, J. / Brownell, J. / Yang, Y. / Stringer, B. / Griffin, R. / Bruzzese, F. / Soucy, T. / Duffy, J. / Rabino, C. / Riceberg, J. / Hoar, K. / Lublinsky, A. / Menon, S. / Sintchak, M. / Bump, N. / Pulukuri, S. / Amidon, B. / Langston, S. / Tirrell, S. / Kuranda, M. / Veiby, P. / Newcomb, J. / Li, P. / Wu, J. / Dick, L. / Greenspan, P. / Galvin, K. / Manfredi, M. / Claibrone, C. / Bence, N.
History
DepositionOct 25, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 1, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ubiquitin-activating enzyme E1 1
B: Ubiquitin
C: Ubiquitin-activating enzyme E1 1
D: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)245,5876
Polymers244,5484
Non-polymers1,0392
Water7,278404
1
A: Ubiquitin-activating enzyme E1 1
B: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,7933
Polymers122,2742
Non-polymers5201
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3990 Å2
ΔGint-10 kcal/mol
Surface area42830 Å2
MethodPISA
2
C: Ubiquitin-activating enzyme E1 1
D: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,7933
Polymers122,2742
Non-polymers5201
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3950 Å2
ΔGint-11 kcal/mol
Surface area41420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)212.485, 172.148, 79.424
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Ubiquitin-activating enzyme E1 1


Mass: 113705.195 Da / Num. of mol.: 2 / Fragment: residues 9-1024 / Mutation: N471M, K519R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c / Gene: UBA1, YKL210W / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P22515, E1 ubiquitin-activating enzyme
#2: Protein Ubiquitin /


Mass: 8568.769 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: UBB / References: UniProt: P0CG53
#3: Chemical ChemComp-61T / [(1~{R},2~{R},3~{S},4~{R})-2,3-bis(oxidanyl)-4-[[2-[3-(trifluoromethylsulfanyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]amino]cyclopentyl]methyl sulfamate / MLN7243


Mass: 519.518 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20F3N5O5S2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 404 / 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: 2.97 Å3/Da / Density % sol: 58.59 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 70 mM Na malonate pH 6.0, 70 mM malic acid, 70 mM Na citrate, 10-15% peg-3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97929 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 17, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 146857 / % possible obs: 98.8 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.056 / Rrim(I) all: 0.151 / Χ2: 1.009 / Net I/av σ(I): 13.534 / Net I/σ(I): 6 / Num. measured all: 1011343
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Diffraction-ID% possible all
2.2-2.286.71.1640.616197
2.28-2.376.70.8870.747197.4
2.37-2.486.80.690.823197.2
2.48-2.616.80.5140.889198.2
2.61-2.776.80.3520.941198.9
2.77-2.996.90.2420.967199.7
2.99-3.296.90.1510.987199.9
3.29-3.7670.1160.99199.9
3.76-4.747.10.1110.9891100
4.74-507.10.0640.995199.5

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
MOLREPphasing
HKLdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3CMM

3cmm


Resolution: 2.2→50 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.91 / SU B: 6.429 / SU ML: 0.157 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.228 / ESU R Free: 0.197
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2559 2842 2 %RANDOM
Rwork0.2163 ---
obs0.2171 139402 95.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 123.25 Å2 / Biso mean: 34.902 Å2 / Biso min: 15.23 Å2
Baniso -1Baniso -2Baniso -3
1--0.34 Å2-0 Å2-0 Å2
2--0.01 Å2-0 Å2
3---0.33 Å2
Refinement stepCycle: final / Resolution: 2.2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15867 0 68 404 16339
Biso mean--35.14 31.68 -
Num. residues----2075
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.01916269
X-RAY DIFFRACTIONr_angle_refined_deg1.3031.96822094
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.73552064
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.38625.056714
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.745152637
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.561565
X-RAY DIFFRACTIONr_chiral_restr0.0840.22541
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.02112305
X-RAY DIFFRACTIONr_mcbond_it3.4123.5268289
X-RAY DIFFRACTIONr_mcangle_it4.7695.27110336
X-RAY DIFFRACTIONr_scbond_it4.2543.6537980
LS refinement shellResolution: 2.198→2.255 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 148 -
Rwork0.282 7383 -
all-7531 -
obs--69.26 %

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