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- PDB-7rm4: Neoantigen p53R175H-specific TCR 6-11 binds to p53R175H-HLA-A2 -

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Basic information

Entry
Database: PDB / ID: 7rm4
TitleNeoantigen p53R175H-specific TCR 6-11 binds to p53R175H-HLA-A2
Components
  • 6-11 T cell receptor alpha chain
  • 6-11 T cell receptor beta chain
  • Beta-2-microglobulin
  • Cellular tumor antigen p53 peptide
  • HLA class I histocompatibility antigen, A alpha chain
KeywordsIMMUNE SYSTEM / TCR-pMHC / Neoantigen / Cancer
Function / homology
Function and homology information


Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity ...Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / histone deacetylase regulator activity / germ cell nucleus / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / regulation of DNA damage response, signal transduction by p53 class mediator / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / T cell mediated cytotoxicity directed against tumor cell target / positive regulation of memory T cell activation / TAP complex binding / negative regulation of glial cell proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / Golgi medial cisterna / mitochondrial DNA repair / T cell lineage commitment / positive regulation of CD8-positive, alpha-beta T cell proliferation / CD8 receptor binding / negative regulation of DNA replication / ER overload response / B cell lineage commitment / positive regulation of cardiac muscle cell apoptotic process / thymocyte apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / positive regulation of execution phase of apoptosis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / antigen processing and presentation of exogenous peptide antigen via MHC class I / Association of TriC/CCT with target proteins during biosynthesis / Zygotic genome activation (ZGA) / necroptotic process / endoplasmic reticulum exit site / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / rRNA transcription / mitophagy / SUMOylation of transcription factors / negative regulation of telomere maintenance via telomerase / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / TAP binding / Transcriptional Regulation by VENTX / DNA damage response, signal transduction by p53 class mediator / response to X-ray / protection from natural killer cell mediated cytotoxicity / replicative senescence / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / neuroblast proliferation / cellular response to UV-C / : / hematopoietic stem cell differentiation / negative regulation of reactive oxygen species metabolic process / chromosome organization / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / T cell proliferation involved in immune response / glial cell proliferation / embryonic organ development / beta-2-microglobulin binding / positive regulation of RNA polymerase II transcription preinitiation complex assembly / Pyroptosis / cis-regulatory region sequence-specific DNA binding / hematopoietic progenitor cell differentiation / cellular response to glucose starvation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cellular response to actinomycin D
Similarity search - Function
Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family ...Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / p53-like transcription factor, DNA-binding / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 / Beta-2-Microglobulin / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / MHC classes I/II-like antigen recognition protein / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
HLA class I histocompatibility antigen, A alpha chain / Cellular tumor antigen p53 / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.33 Å
AuthorsWu, D. / Mariuzza, R.A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI129893 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM126299 United States
CitationJournal: J.Biol.Chem. / Year: 2022
Title: T cell receptors employ diverse strategies to target a p53 cancer neoantigen.
Authors: Wu, D. / Gowathaman, R. / Pierce, B.G. / Mariuzza, R.A.
History
DepositionJul 26, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 9, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: Database references / Category: citation
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 16, 2022Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HLA class I histocompatibility antigen, A alpha chain
B: Beta-2-microglobulin
C: Cellular tumor antigen p53 peptide
D: 6-11 T cell receptor beta chain
E: 6-11 T cell receptor alpha chain
F: HLA class I histocompatibility antigen, A alpha chain
G: Beta-2-microglobulin
H: Cellular tumor antigen p53 peptide
I: 6-11 T cell receptor beta chain
J: 6-11 T cell receptor alpha chain
K: HLA class I histocompatibility antigen, A alpha chain
L: Beta-2-microglobulin
M: Cellular tumor antigen p53 peptide
N: 6-11 T cell receptor beta chain
O: 6-11 T cell receptor alpha chain
P: HLA class I histocompatibility antigen, A alpha chain
Q: Beta-2-microglobulin
R: Cellular tumor antigen p53 peptide
S: 6-11 T cell receptor beta chain
T: 6-11 T cell receptor alpha chain


Theoretical massNumber of molelcules
Total (without water)383,41120
Polymers383,41120
Non-polymers00
Water00
1
A: HLA class I histocompatibility antigen, A alpha chain
B: Beta-2-microglobulin
C: Cellular tumor antigen p53 peptide
D: 6-11 T cell receptor beta chain
E: 6-11 T cell receptor alpha chain


Theoretical massNumber of molelcules
Total (without water)95,8535
Polymers95,8535
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
F: HLA class I histocompatibility antigen, A alpha chain
G: Beta-2-microglobulin
H: Cellular tumor antigen p53 peptide
I: 6-11 T cell receptor beta chain
J: 6-11 T cell receptor alpha chain


Theoretical massNumber of molelcules
Total (without water)95,8535
Polymers95,8535
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
K: HLA class I histocompatibility antigen, A alpha chain
L: Beta-2-microglobulin
M: Cellular tumor antigen p53 peptide
N: 6-11 T cell receptor beta chain
O: 6-11 T cell receptor alpha chain


Theoretical massNumber of molelcules
Total (without water)95,8535
Polymers95,8535
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
P: HLA class I histocompatibility antigen, A alpha chain
Q: Beta-2-microglobulin
R: Cellular tumor antigen p53 peptide
S: 6-11 T cell receptor beta chain
T: 6-11 T cell receptor alpha chain


Theoretical massNumber of molelcules
Total (without water)95,8535
Polymers95,8535
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)127.226, 55.144, 304.877
Angle α, β, γ (deg.)90.000, 98.740, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 1 through 57 or (resid 58...
21chain F
31chain K
41chain P
12chain B
22(chain G and resid 1 through 99)
32chain L
42chain Q
13chain C
23chain H
33chain M
43chain R
14(chain D and (resid 2 through 227 or (resid 228...
24(chain I and (resid 2 through 82 or (resid 83...
34(chain N and (resid 2 through 82 or (resid 83...
44(chain S and (resid 2 through 82 or (resid 83...
15chain E
25chain J
35chain O
45chain T

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111GLYGLYPROPRO(chain A and (resid 1 through 57 or (resid 58...AA1 - 571 - 57
121GLUGLUGLUGLU(chain A and (resid 1 through 57 or (resid 58...AA5858
131GLYGLYGLUGLU(chain A and (resid 1 through 57 or (resid 58...AA1 - 2751 - 275
141GLYGLYGLUGLU(chain A and (resid 1 through 57 or (resid 58...AA1 - 2751 - 275
151GLYGLYGLUGLU(chain A and (resid 1 through 57 or (resid 58...AA1 - 2751 - 275
161GLYGLYGLUGLU(chain A and (resid 1 through 57 or (resid 58...AA1 - 2751 - 275
211GLYGLYGLUGLUchain FFF1 - 2751 - 275
311GLYGLYGLUGLUchain KKK1 - 2751 - 275
411GLYGLYGLUGLUchain PPP1 - 2751 - 275
112METMETMETMETchain BBB1 - 1001 - 100
212METMETASPASP(chain G and resid 1 through 99)GG1 - 991 - 99
312METMETMETMETchain LLL1 - 1001 - 100
412METMETMETMETchain QQQ1 - 1001 - 100
113HISHISCYSCYSchain CCC1 - 91 - 9
213HISHISCYSCYSchain HHH1 - 91 - 9
313HISHISCYSCYSchain MMM1 - 91 - 9
413HISHISCYSCYSchain RRR1 - 91 - 9
114ALAALAASPASP(chain D and (resid 2 through 227 or (resid 228...DD2 - 2273 - 228
124ARGARGALAALA(chain D and (resid 2 through 227 or (resid 228...DD228 - 229229 - 230
134ALAALAALAALA(chain D and (resid 2 through 227 or (resid 228...DD2 - 2443 - 245
144ALAALAALAALA(chain D and (resid 2 through 227 or (resid 228...DD2 - 2443 - 245
154ALAALAALAALA(chain D and (resid 2 through 227 or (resid 228...DD2 - 2443 - 245
164ALAALAALAALA(chain D and (resid 2 through 227 or (resid 228...DD2 - 2443 - 245
214ALAALAALAALA(chain I and (resid 2 through 82 or (resid 83...II2 - 823 - 83
224LYSLYSLYSLYS(chain I and (resid 2 through 82 or (resid 83...II8384
234ALAALAALAALA(chain I and (resid 2 through 82 or (resid 83...II2 - 2443 - 245
244ALAALAALAALA(chain I and (resid 2 through 82 or (resid 83...II2 - 2443 - 245
254ALAALAALAALA(chain I and (resid 2 through 82 or (resid 83...II2 - 2443 - 245
264ALAALAALAALA(chain I and (resid 2 through 82 or (resid 83...II2 - 2443 - 245
314ALAALAALAALA(chain N and (resid 2 through 82 or (resid 83...NN2 - 823 - 83
324LYSLYSLYSLYS(chain N and (resid 2 through 82 or (resid 83...NN8384
334ALAALAALAALA(chain N and (resid 2 through 82 or (resid 83...NN2 - 2443 - 245
344ALAALAALAALA(chain N and (resid 2 through 82 or (resid 83...NN2 - 2443 - 245
354ALAALAALAALA(chain N and (resid 2 through 82 or (resid 83...NN2 - 2443 - 245
414ALAALAALAALA(chain S and (resid 2 through 82 or (resid 83...SS2 - 823 - 83
424LYSLYSLYSLYS(chain S and (resid 2 through 82 or (resid 83...SS8384
434ALAALAALAALA(chain S and (resid 2 through 82 or (resid 83...SS2 - 2443 - 245
115LYSLYSPROPROchain EEE3 - 2024 - 203
215LYSLYSPROPROchain JJJ3 - 2024 - 203
315LYSLYSPROPROchain OOO3 - 2024 - 203
415LYSLYSPROPROchain TTT3 - 2024 - 203

NCS ensembles :
ID
1
2
3
4
5

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Components

#1: Protein
HLA class I histocompatibility antigen, A alpha chain / Human leukocyte antigen A / HLA-A


Mass: 31854.203 Da / Num. of mol.: 4 / Fragment: UNP residues 25-299
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A, HLAA / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P04439
#2: Protein
Beta-2-microglobulin


Mass: 11879.356 Da / Num. of mol.: 4 / Fragment: UNP residues 21-119
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P61769
#3: Protein/peptide
Cellular tumor antigen p53 peptide / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 1114.320 Da / Num. of mol.: 4 / Mutation: R175H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TP53, P53 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P04637
#4: Protein
6-11 T cell receptor beta chain


Mass: 27662.949 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: 6-11 T cell receptor beta chain / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
#5: Protein
6-11 T cell receptor alpha chain


Mass: 23342.012 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: 6-11 T cell receptor alpha chain / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)

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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: 2.76 Å3/Da / Density % sol: 55.39 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 20% (w/v) PEG 3350, 0.1 M Bis-Tris propane (pH 8.5), and 0.2 M Potassium thiocyanate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.33→49.319 Å / Num. obs: 60837 / % possible obs: 92.6 % / Redundancy: 4.8 % / CC1/2: 0.992 / Net I/σ(I): 10.3
Reflection shellResolution: 3.33→3.45 Å / Num. unique obs: 4526 / CC1/2: 0.737

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WKF, 6OVN, 6VR5
Resolution: 3.33→49.319 Å / SU ML: 0.5 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 34.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2949 2703 4.65 %
Rwork0.237 55378 -
obs0.2397 58081 92.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 144.11 Å2 / Biso mean: 50.5848 Å2 / Biso min: 10.05 Å2
Refinement stepCycle: final / Resolution: 3.33→49.319 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms26474 0 0 0 26474
Num. residues----3308
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A3376X-RAY DIFFRACTION2.015TORSIONAL
12F3376X-RAY DIFFRACTION2.015TORSIONAL
13K3376X-RAY DIFFRACTION2.015TORSIONAL
14P3376X-RAY DIFFRACTION2.015TORSIONAL
21B1196X-RAY DIFFRACTION2.015TORSIONAL
22G1196X-RAY DIFFRACTION2.015TORSIONAL
23L1196X-RAY DIFFRACTION2.015TORSIONAL
24Q1196X-RAY DIFFRACTION2.015TORSIONAL
31C104X-RAY DIFFRACTION2.015TORSIONAL
32H104X-RAY DIFFRACTION2.015TORSIONAL
33M104X-RAY DIFFRACTION2.015TORSIONAL
34R104X-RAY DIFFRACTION2.015TORSIONAL
41D2912X-RAY DIFFRACTION2.015TORSIONAL
42I2912X-RAY DIFFRACTION2.015TORSIONAL
43N2912X-RAY DIFFRACTION2.015TORSIONAL
44S2912X-RAY DIFFRACTION2.015TORSIONAL
51E2400X-RAY DIFFRACTION2.015TORSIONAL
52J2400X-RAY DIFFRACTION2.015TORSIONAL
53O2400X-RAY DIFFRACTION2.015TORSIONAL
54T2400X-RAY DIFFRACTION2.015TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.33-3.39050.39121150.3319209167
3.3905-3.45570.39031290.3194241377
3.4557-3.52630.38291310.3126258985
3.5263-3.60290.36051500.3153285992
3.6029-3.68670.37111440.3097302796
3.6867-3.77890.34461380.3009299598
3.7789-3.8810.35081600.2811305598
3.881-3.99510.33671600.2747307398
3.9951-4.1240.37351320.2574299097
4.124-4.27130.29071530.2451304496
4.2713-4.44230.33531170.2257294895
4.4423-4.64430.24311380.2066293693
4.6443-4.88890.24061340.1874287592
4.8889-5.19490.25451430.189294394
5.1949-5.59550.25121680.1953304396
5.5955-6.15770.25611260.2053310697
6.1577-7.04650.30711470.2165316399
7.0465-8.86940.24631610.1959306996
8.8694-49.3190.19811570.1905315994

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