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- PDB-8rxb: Human UPF1 CH domain in complex with SMG6 peptide -

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Basic information

Entry
Database: PDB / ID: 8rxb
TitleHuman UPF1 CH domain in complex with SMG6 peptide
Components
  • Regulator of nonsense transcripts 1
  • Telomerase-binding protein EST1A
KeywordsRNA BINDING PROTEIN / UPF1 Nonsense-mediated mRNA decay mRNA surveillance and turnover
Function / homology
Function and homology information


regulation of dephosphorylation / : / double-stranded DNA helicase activity / supraspliceosomal complex / positive regulation of mRNA cis splicing, via spliceosome / negative regulation of telomere capping / exon-exon junction complex / telomere maintenance via semi-conservative replication / positive regulation of mRNA catabolic process / cell cycle phase transition ...regulation of dephosphorylation / : / double-stranded DNA helicase activity / supraspliceosomal complex / positive regulation of mRNA cis splicing, via spliceosome / negative regulation of telomere capping / exon-exon junction complex / telomere maintenance via semi-conservative replication / positive regulation of mRNA catabolic process / cell cycle phase transition / regulation of translational termination / histone mRNA catabolic process / regulation of telomere maintenance via telomerase / 3'-UTR-mediated mRNA destabilization / telomerase holoenzyme complex / telomerase RNA binding / regulation of telomere maintenance / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / DNA duplex unwinding / nuclear-transcribed mRNA catabolic process / telomeric DNA binding / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / cellular response to interleukin-1 / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / mRNA export from nucleus / ribonucleoprotein complex binding / DNA polymerase binding / RNA endonuclease activity / helicase activity / P-body / cellular response to lipopolysaccharide / DNA replication / DNA helicase / chromosome, telomeric region / RNA helicase activity / Hydrolases; Acting on ester bonds / RNA helicase / DNA repair / chromatin binding / protein-containing complex binding / chromatin / nucleolus / perinuclear region of cytoplasm / ATP hydrolysis activity / RNA binding / zinc ion binding / nucleoplasm / ATP binding / nucleus / metal ion binding / cytoplasm / cytosol
Similarity search - Function
Est1/Ebs1-like / Telomerase activating protein Est1-like, N-terminal / Telomerase activating protein Est1 / DNA/RNA-binding domain, Est1-type / Est1 DNA/RNA binding domain / Upf1 cysteine-histidine-rich (CH-rich) domain profile. / RNA helicase UPF1, 1B domain / RNA helicase (UPF2 interacting domain) / RNA helicase UPF1, 1B domain / RNA helicase UPF1, Cys/His rich zinc-binding domain ...Est1/Ebs1-like / Telomerase activating protein Est1-like, N-terminal / Telomerase activating protein Est1 / DNA/RNA-binding domain, Est1-type / Est1 DNA/RNA binding domain / Upf1 cysteine-histidine-rich (CH-rich) domain profile. / RNA helicase UPF1, 1B domain / RNA helicase (UPF2 interacting domain) / RNA helicase UPF1, 1B domain / RNA helicase UPF1, Cys/His rich zinc-binding domain / PIN domain / : / DNA2/NAM7 helicase, helicase domain / DNA2/NAM7-like helicase / AAA domain / Large family of predicted nucleotide-binding domains / PIN domain / Helicase/UvrB, N-terminal / Type III restriction enzyme, res subunit / PIN-like domain superfamily / Tetratricopeptide-like helical domain superfamily / DNA2/NAM7 helicase-like, C-terminal / AAA domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Telomerase-binding protein EST1A / Regulator of nonsense transcripts 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsLanger, L. / Basquin, J. / Conti, E.
Funding supportEuropean Union, Germany, 2items
OrganizationGrant numberCountry
European Research Council (ERC)101054447European Union
German Research Foundation (DFG)SFB1035) Germany
CitationJournal: Nucleic Acids Res / Year: 2024
Title: UPF1 helicase orchestrates mutually exclusive interactions with the SMG6 endonuclease and UPF2.
Authors: Lukas M Langer / Katharina Kurscheidt / Jérôme Basquin / Fabien Bonneau / Iuliia Iermak / Claire Basquin / Elena Conti /
Abstract: Nonsense-mediated mRNA decay (NMD) is a conserved co-translational mRNA surveillance and turnover pathway across eukaryotes. NMD has a central role in degrading defective mRNAs and also regulates the ...Nonsense-mediated mRNA decay (NMD) is a conserved co-translational mRNA surveillance and turnover pathway across eukaryotes. NMD has a central role in degrading defective mRNAs and also regulates the stability of a significant portion of the transcriptome. The pathway is organized around UPF1, an RNA helicase that can interact with several NMD-specific factors. In human cells, degradation of the targeted mRNAs begins with a cleavage event that requires the recruitment of the SMG6 endonuclease to UPF1. Previous studies have identified functional links between SMG6 and UPF1, but the underlying molecular mechanisms have remained elusive. Here, we used mass spectrometry, structural biology and biochemical approaches to identify and characterize a conserved short linear motif in SMG6 that interacts with the cysteine/histidine-rich (CH) domain of UPF1. Unexpectedly, we found that the UPF1-SMG6 interaction is precluded when the UPF1 CH domain is engaged with another NMD factor, UPF2. Based on cryo-EM data, we propose that the formation of distinct SMG6-containing and UPF2-containing NMD complexes may be dictated by different conformational states connected to the RNA-binding status of UPF1. Our findings rationalize a key event in metazoan NMD and advance our understanding of mechanisms regulating activity and guiding substrate recognition by the SMG6 endonuclease.
History
DepositionFeb 6, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 15, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Regulator of nonsense transcripts 1
F: Telomerase-binding protein EST1A
A: Regulator of nonsense transcripts 1
B: Telomerase-binding protein EST1A
D: Regulator of nonsense transcripts 1
G: Telomerase-binding protein EST1A
I: Regulator of nonsense transcripts 1
J: Telomerase-binding protein EST1A
L: Regulator of nonsense transcripts 1
N: Telomerase-binding protein EST1A
P: Regulator of nonsense transcripts 1
Q: Telomerase-binding protein EST1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,39125
Polymers126,54112
Non-polymers85013
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.165, 90.677, 92.291
Angle α, β, γ (deg.)90.000, 113.361, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 4 through 36 or (resid 37...
d_2ens_1(chain "D" and (resid 4 through 37 or (resid 38...
d_3ens_1(chain "E" and (resid 4 through 36 or (resid 37...
d_4ens_1(chain "I" and (resid 4 through 36 or (resid 37...
d_5ens_1(chain "L" and (resid 4 through 36 or (resid 37...
d_6ens_1(chain "P" and (resid 4 through 36 or (resid 37...
d_1ens_2chain "B"
d_2ens_2chain "F"
d_3ens_2chain "G"
d_4ens_2chain "J"
d_5ens_2chain "N"
d_6ens_2chain "Q"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1LEULEUPROPROAC4 - 844 - 84
d_12ens_1VALVALSERSERAC90 - 16090 - 160
d_13ens_1ZNZNZNZNAP201
d_21ens_1LEULEUPROPRODE4 - 844 - 84
d_22ens_1VALVALSERSERDE90 - 16090 - 160
d_23ens_1ZNZNZNZNDR201
d_31ens_1LEULEUPROPROEA4 - 844 - 84
d_32ens_1VALVALSERSEREA90 - 16090 - 160
d_33ens_1ZNZNZNZNEM201
d_41ens_1LEULEUPROPROIG4 - 844 - 84
d_42ens_1VALVALSERSERIG90 - 16090 - 160
d_43ens_1ZNZNZNZNIT201
d_51ens_1LEULEUPROPROLI4 - 844 - 84
d_52ens_1VALVALSERSERLI90 - 16090 - 160
d_53ens_1ZNZNZNZNLV201
d_61ens_1LEULEUPROPROPK4 - 844 - 84
d_62ens_1VALVALSERSERPK90 - 16090 - 160
d_63ens_1ZNZNZNZNPX201
d_11ens_2ARGARGALAALABD406 - 4133 - 10
d_21ens_2ARGARGALAALAFB406 - 4133 - 10
d_31ens_2ARGARGALAALAGF406 - 4133 - 10
d_41ens_2ARGARGALAALAJH406 - 4133 - 10
d_51ens_2ARGARGALAALANJ406 - 4133 - 10
d_61ens_2ARGARGALAALAQL406 - 4133 - 10

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.230109551934, 0.00377504031257, -0.973157409251), (0.043210632417, 0.998966585959, 0.0140926002996), (0.972204934854, -0.0452935890355, 0.229708631613)14.2198771779, 12.128775014, 4.88754224784
2given(-0.221641861599, -0.0279585509416, 0.974727246267), (-0.0428755637414, -0.99834275263, -0.0383853397087), (0.974185080578, -0.050299778329, 0.220075807574)-7.90093154479, -14.5361194647, 5.79469411148
3given(0.494332139236, 0.045140515887, 0.868100264914), (0.00154422614218, 0.998603599567, -0.0528059305085), (-0.869271736273, 0.0274442117157, 0.493572146458)-42.4289738379, -13.8940051436, 85.6306742916
4given(-0.999654100052, 0.0228645153599, -0.0129959296522), (-0.0233157955503, -0.999090366305, 0.0357045324178), (-0.0121677412868, 0.0359951926607, 0.999277885364)7.29170612429, -4.03265378048, -0.00315383137411
5given(-0.752599452283, 0.0755293749741, -0.654132538511), (-0.0578855692606, -0.997142681189, -0.0485359065333), (-0.655929359988, 0.00133673769061, 0.754821096577)55.74287582, 15.8650553711, 73.4222568258
6given(-0.18740089967, 0.0723578124942, 0.979614847669), (-0.0273779822602, -0.997280518715, 0.0684252371532), (0.981901903904, -0.0139969269186, 0.188872277338)-8.07088944061, -17.7753918872, 6.64381060602
7given(0.151483464419, -0.0281763628957, -0.988058122066), (0.040400005198, 0.998934871762, -0.0222926346275), (0.987633838823, -0.036540587743, 0.152460440311)16.9933649486, 13.2899286376, 6.06845754344
8given(0.630679470348, -0.0469018704022, 0.77462482547), (-0.0558438031529, 0.992841438955, 0.105580996123), (-0.774031572567, -0.109845762984, 0.623545534042)-46.6725983128, -14.9519986951, 78.0844928022
9given(-0.999142190399, -0.0402804251916, -0.00961096828793), (0.0388465834999, -0.992079025883, 0.119457730403), (-0.01434664823, 0.118981905133, 0.99279276787)6.84005432673, -8.32985961908, 0.723155267491
10given(-0.7997076155, 0.0796377690952, -0.595084494374), (-0.0647884379121, -0.99682273954, -0.04633448229), (-0.596883730742, 0.0015005564687, 0.802326342772)56.1048555815, 15.5992144252, 70.3440741638

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Components

#1: Protein
Regulator of nonsense transcripts 1 / ATP-dependent helicase RENT1 / Nonsense mRNA reducing factor 1 / NORF1 / Up-frameshift suppressor 1 ...ATP-dependent helicase RENT1 / Nonsense mRNA reducing factor 1 / NORF1 / Up-frameshift suppressor 1 homolog / hUpf1


Mass: 19482.277 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UPF1, KIAA0221, RENT1 / Production host: Escherichia coli (E. coli) / Strain (production host): E.Coli pRare / References: UniProt: Q92900, DNA helicase, RNA helicase
#2: Protein/peptide
Telomerase-binding protein EST1A / Ever shorter telomeres 1A / hEST1A / Nonsense mediated mRNA decay factor SMG6 / Smg-6 homolog / hSmg5/7a


Mass: 1607.920 Da / Num. of mol.: 6 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q86US8, Hydrolases; Acting on ester bonds
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.65 Å3/Da / Density % sol: 53.51 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: solution (28% (w/v) PEG 3500, 0.2M Lithium sulfate and 0.1 M Tris pH 7.8)
PH range: 7.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 31, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.597→43.44 Å / Num. obs: 75047 / % possible obs: 93.69 % / Redundancy: 2 % / Biso Wilson estimate: 54.01 Å2 / CC1/2: 0.99 / Net I/σ(I): 6.91
Reflection shellResolution: 2.6→2.63 Å / Num. unique obs: 2523 / CC1/2: 0.84

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Processing

Software
NameVersionClassification
PHENIX1.21rc1_5109refinement
XDSdata scaling
XSCALEdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→43.44 Å / SU ML: 0.3872 / Cross valid method: FREE R-VALUE / σ(F): 1.05 / Phase error: 33.2292
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2947 3750 5 %
Rwork0.2811 71280 -
obs0.2818 75030 93.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 61.08 Å2
Refinement stepCycle: LAST / Resolution: 2.6→43.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7182 0 13 0 7195
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00757332
X-RAY DIFFRACTIONf_angle_d1.10519944
X-RAY DIFFRACTIONf_chiral_restr0.06351130
X-RAY DIFFRACTIONf_plane_restr0.00921266
X-RAY DIFFRACTIONf_dihedral_angle_d14.4762662
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2CAX-RAY DIFFRACTIONTorsion NCS1.01522224925
ens_1d_3CAX-RAY DIFFRACTIONTorsion NCS1.14801178372
ens_1d_4CAX-RAY DIFFRACTIONTorsion NCS1.02770994879
ens_1d_5CAX-RAY DIFFRACTIONTorsion NCS1.00097848596
ens_1d_6CAX-RAY DIFFRACTIONTorsion NCS1.02442561245
ens_2d_2DBX-RAY DIFFRACTIONTorsion NCS1.15167821808
ens_2d_3DBX-RAY DIFFRACTIONTorsion NCS1.13296465911
ens_2d_4DBX-RAY DIFFRACTIONTorsion NCS1.61518939944
ens_2d_5DBX-RAY DIFFRACTIONTorsion NCS1.16777060429
ens_2d_6DBX-RAY DIFFRACTIONTorsion NCS1.01410998668
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.630.35181280.31362395X-RAY DIFFRACTION83.21
2.63-2.660.3851450.30612773X-RAY DIFFRACTION99.18
2.66-2.70.31331440.31272737X-RAY DIFFRACTION98.36
2.7-2.740.33891480.31282869X-RAY DIFFRACTION98.92
2.74-2.780.36911440.33352732X-RAY DIFFRACTION99.07
2.78-2.820.32971490.32582802X-RAY DIFFRACTION98.4
2.82-2.870.34821420.33632732X-RAY DIFFRACTION98.16
2.87-2.920.37361500.32332804X-RAY DIFFRACTION98.07
2.92-2.970.30151450.31922697X-RAY DIFFRACTION97.33
2.97-3.030.36421430.3152706X-RAY DIFFRACTION96.71
3.03-3.090.2841430.32242743X-RAY DIFFRACTION96.75
3.09-3.160.32941400.30772700X-RAY DIFFRACTION95.85
3.16-3.230.38391400.31712714X-RAY DIFFRACTION95.45
3.23-3.310.33321410.32852653X-RAY DIFFRACTION94.23
3.31-3.40.3431360.30882621X-RAY DIFFRACTION92.95
3.4-3.50.31491370.28952568X-RAY DIFFRACTION90.99
3.5-3.620.32551330.2862527X-RAY DIFFRACTION90.11
3.62-3.750.2891350.28212531X-RAY DIFFRACTION91.08
3.75-3.90.27751320.27392550X-RAY DIFFRACTION90.46
3.9-4.070.25751360.25622555X-RAY DIFFRACTION90.7
4.07-4.290.2461340.2542581X-RAY DIFFRACTION90.14
4.29-4.560.2451370.24642495X-RAY DIFFRACTION89.95
4.56-4.910.23971310.2352544X-RAY DIFFRACTION89.86
4.91-5.40.24071410.25522555X-RAY DIFFRACTION90.65
5.4-6.180.28141330.27222560X-RAY DIFFRACTION91.2
6.18-7.780.31861300.28342553X-RAY DIFFRACTION90.64
7.78-43.440.29491330.26572583X-RAY DIFFRACTION91.36

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