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- EMDB-13676: Human SMG1-8-9 kinase complex bound to a SMG1 inhibitor - SMG1 body -

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Basic information

Entry
Database: EMDB / ID: EMD-13676
TitleHuman SMG1-8-9 kinase complex bound to a SMG1 inhibitor - SMG1 body
Map data
Sample
  • Complex: SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor
    • Protein or peptide: Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1
  • Ligand: INOSITOL HEXAKISPHOSPHATEPhytic acid
  • Ligand: 1-[4-[4-[2-[[4-chloranyl-3-(diethylsulfamoyl)phenyl]amino]pyrimidin-4-yl]pyridin-2-yl]phenyl]-3-methyl-urea
Function / homology
Function and homology information


diacylglycerol-dependent serine/threonine kinase activity / chromatoid body / regulation of telomere maintenance / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / telomeric DNA binding / phosphatidylinositol phosphate biosynthetic process / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / mRNA export from nucleus / peptidyl-serine phosphorylation / protein autophosphorylation ...diacylglycerol-dependent serine/threonine kinase activity / chromatoid body / regulation of telomere maintenance / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / telomeric DNA binding / phosphatidylinositol phosphate biosynthetic process / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / mRNA export from nucleus / peptidyl-serine phosphorylation / protein autophosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / DNA damage response / RNA binding / nucleoplasm / ATP binding / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Serine/threonine-protein kinase SMG1 / Serine/threonine-protein kinase SMG1, N-terminal / SMG1, PIKK catalytic domain / Serine/threonine-protein kinase smg-1 / Serine/threonine-protein kinase SMG1 N-terminal / Rapamycin binding domain / FATC domain / FATC / FATC domain / PIK-related kinase ...Serine/threonine-protein kinase SMG1 / Serine/threonine-protein kinase SMG1, N-terminal / SMG1, PIKK catalytic domain / Serine/threonine-protein kinase smg-1 / Serine/threonine-protein kinase SMG1 N-terminal / Rapamycin binding domain / FATC domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Armadillo-like helical / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Serine/threonine-protein kinase SMG1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsLanger LM / Conti E
Funding support Germany, 1 items
OrganizationGrant numberCountry
Not funded Germany
CitationJournal: Elife / Year: 2021
Title: Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8.
Authors: Lukas M Langer / Fabien Bonneau / Yair Gat / Elena Conti /
Abstract: The PI3K-related kinase (PIKK) SMG1 monitors the progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 ...The PI3K-related kinase (PIKK) SMG1 monitors the progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 is impaired by small molecule inhibitors, is reduced by the SMG1 interactors SMG8 and SMG9, and is downregulated by the so-called SMG1 insertion domain. However, the molecular basis for this complex regulatory network has remained elusive. Here, we present cryo-electron microscopy reconstructions of human SMG1-9 and SMG1-8-9 complexes bound to either a SMG1 inhibitor or a non-hydrolyzable ATP analog at overall resolutions ranging from 2.8 to 3.6 Å. These structures reveal the basis with which a small molecule inhibitor preferentially targets SMG1 over other PIKKs. By comparison with our previously reported substrate-bound structure (Langer et al.,2020), we show that the SMG1 insertion domain can exert an autoinhibitory function by directly blocking the substrate-binding path as well as overall access to the SMG1 kinase active site. Together with biochemical analysis, our data indicate that SMG1 autoinhibition is stabilized by the presence of SMG8. Our results explain the specific inhibition of SMG1 by an ATP-competitive small molecule, provide insights into regulation of its kinase activity within the NMD pathway, and expand the understanding of PIKK regulatory mechanisms in general.
History
DepositionOct 6, 2021-
Header (metadata) releaseDec 1, 2021-
Map releaseDec 1, 2021-
UpdateDec 1, 2021-
Current statusDec 1, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.586
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.586
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7pw6
  • Surface level: 0.586
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13676.png

Downloads & links

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Map

FileDownload / File: emd_13676.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.8512 Å
Density
Contour LevelBy AUTHOR: 0.586 / Movie #1: 0.586
Minimum - Maximum-2.795148 - 5.0242047
Average (Standard dev.)0.0033192309 (±0.07293735)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 326.86078 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.851200520833330.851200520833330.85120052083333
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z326.861326.861326.861
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ352352352
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-2.7955.0240.003

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Supplemental data

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Sample components

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Entire : SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor

EntireName: SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor
Components
  • Complex: SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor
    • Protein or peptide: Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1
  • Ligand: INOSITOL HEXAKISPHOSPHATEPhytic acid
  • Ligand: 1-[4-[4-[2-[[4-chloranyl-3-(diethylsulfamoyl)phenyl]amino]pyrimidin-4-yl]pyridin-2-yl]phenyl]-3-methyl-urea

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Supramolecule #1: SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor

SupramoleculeName: SMG1-SMG8-SMG9 kinase complex bound to a SMG1 inhibitor
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightTheoretical: 597 KDa

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Macromolecule #1: Serine/threonine-protein kinase SMG1,Serine/threonine-protein kin...

MacromoleculeName: Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase ...Name: Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1,Serine/threonine-protein kinase SMG1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 320.901969 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ANTLVEDVNI CLQACSSLHA LSSSLPDDLL QRCVDVCRVQ LVHSGTRIRQ AFGKLLKSIP LDVVLSNNNH TEIQEISLAL RSHMSKAPS NTFHPQDFSD VISFILYGNS HRTGKDNWLE RLFYSCQRLD KRDQSTIPRN LLKTDAVLWQ WAIWEAAQFT V LSKLRTPL ...String:
ANTLVEDVNI CLQACSSLHA LSSSLPDDLL QRCVDVCRVQ LVHSGTRIRQ AFGKLLKSIP LDVVLSNNNH TEIQEISLAL RSHMSKAPS NTFHPQDFSD VISFILYGNS HRTGKDNWLE RLFYSCQRLD KRDQSTIPRN LLKTDAVLWQ WAIWEAAQFT V LSKLRTPL GRAQDTFQTI EGIIRSLAAH TLNPDQDVSQ WTTADNDEGH GNNQLRLVLL LQYLENLEKL MYNAYEGCAN AL TSPPKVI RTFFYTNRQT CQDWLTRIRL SIMRVGLLAG QPAVTVRHGF DLLTEMKTTS LSQGNELEVT IMMVVEALCE LHC PEAIQG IAVWSSSIVG KNLLWINSVA QQAEGRFEKA SVEYQEHLCA MTGVDCCISS FDKSVLTLAN AGRNSASPKH SLNG ESRKT VLSKPTDSSP EVINYLGNKA CECYISIADW AAVQEWQNSI HDLKKSTSST SLNLKADFNY IKSLSSFESG KFVEC TEQL ELLPGENINL LAGGSKEKIN MKKLLPNMLS PDPRELQKSI EVQLLRSSVC LATALNPIEQ DQKWQSITEN VVKYLK QTS RIAIGPLRLS TLTVSQSLPV LSTLQLYCSS ALENTVSNRL STEDCLIPLF SEALRSCKQH DVRPWMQALR YTMYQNQ LL EKIKEQTVPI RSHLMELGLT AAKFARKRGN VSLATRLLAQ CSEVQLGKTT TAQDLVQHFK KLSTQGQVDE KWGPELDI E KTKLLYTAGQ STHAMEMLSS CAISFCKSVK AEYAVAKSIL TLAKWIQAEW KEISGQLKQV YRAQHQQNFT GLSTLSKNI LTLIELPSVN TMEEEYPRIE SESTVHIGVG EPDFILGQLY HLSSVQAPEV AKSWAALASW AYRWGRKVVD NAS(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)EGV IKVWRKVVDR IFSLYKLSCS AYFTFLKLNA GQIPLDEDDP RL HLSHRVE QSTDDMIVMA TLRLLRLLVK HAGELRQYLE HGLETTPTAP WRGIIPQLFS RLNHPEVYVR QSICNLLCRV AQD SPHLIL YPAIVGTISL SSESQASGNK FSTAIPTLLG NIQGEELLVS ECEGGSPPAS QDSNKDEPKS GLNEDQAMMQ DCYS KIVDK LSSANPTMVL QVQMLVAELR RVTVLWDELW LGVLLQQHMY VL(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)PHEKWFQD NYGDAIENAL EKLK(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)YIL RLEEISPWLA AMTNTEIALP GEVSARDTVT IHSVGGTITI LPTKTKP KK LLFLGSDGKS YPYLFKGLED LHLDERIMQF LSIVNTMFAT INRQETPRFH ARHYSVTPLG TRSGLIQWVD GATPLFGL Y KRWQQREAAL QAQKAQDSYQ TPQNPGIVPR PSELYYSKIG PALKTVGLSL DVSRRDWPLH VMKAVLEELM EATPPNLLA KELWSSCTTP DEWWRVTQSY ARSTAVMSMV GYIIGLGDRH LDNVLIDMTT GEVVHIDYNV CFEKGKSLRV PEKVPFRMTQ NIETALGVT GVEGVFRLSC EQVLHIMRRG RETLLTLLEA FVYDPLVDWT AGGEAGFAGA VYGGGGQQAE SKQSKREMER E ITRSLFSS RVAEIKVNWF KNRDEMLVVL PKLDGSLDEY LSLQEQLTDV EKLQGKLLEE IEFLEGAEGV DHPSHTLQHR YS EHTQLQT QQRAVQEAIQ VKLNEFEQWI THYQAAFNNL EATQLASLLQ EISTQMDLGP PSYVPATAFL QNAGQAHLIS QCE QLEGEV GALLQQRRSV LRGCLEQLHH YATVALQYPK AIFQKHRIEQ WKTWMEELIC NTTVERCQEL YRKYEMQYAP QPPP TVCQF ITATEMTLQR YAADINSRLI RQVERLKQEA VTVPVCEDQL KEIERCIKVF LHENGEEGSL SLASVIISAL CTLTR RNLM MEGAASSAGE QLVDLTSRDG AWFLEELCSM SGNVTCLVQL LKQCHLVPQD LDIPNPMEAS ETVHLANGVY TSLQEL NSN FRQIIFPEAL RCLMKGEYTL ESMLHELDGL IEQTTDGVPL QTLVESLQAY LRNAAMGLEE ETHAHYIDVA RLLHAQY GE LIQPRNGSVD ETPKMSAGQM LLVAFDGMFA QVETAFSLLV EKLNKMEIPI AWRKIDIIRE ARSTQVNFFD DDNHRQVL E EIFFLKRLQT IKEFFRLCGT FSKTLSGSSS LEDQNTVNGP VQIVNVKTLF RNSCFSEDQM AKPIKAFTAD FVRQLLIGL PNQALGLTLC SFISALGVDI IAQVEAKDFG AESKVSVDDL CKKAVEHNIQ IGKFSQLVMN RATVLASSYD TAWKKHDLVR RLETSISSC KTSLQRVQLH IAMFQWQHED LLINRPQAMS VTPPPRSAIL TSMKKKLHTL SQIETSIATV QEKLAALESS I EQRLKWAG GANPALAPVL QDFEATIAER RNLVLKESQR ASQVTFLCSN IIHFESLRTR TAEALNLDAA LFELIKRCQQ MC SFASQFN SSVSELELRL LQRVDTGLEH PIGSSEWLLS AHKQLTQDMS TQRAIQTEKE QQIETVCETI QNLVDNIKTV LTG HNRQLG DVKHLLKAMA KDEEAALADG EDVPYENSVR QFLGEYKSWQ DNIQTVLFTL VQAMGQVRSQ EHVEMLQEIT PTLK ELKTQ SQSIYNNLVS FASPLVTDAT NECSSPTSSA TYQPSFAAAV RSNTGQKTQP DVMSQNARKL IQKNLATSAD TPPST VPGT GKSVACSPKK AVRDPKTGKA VQERNSYAVS VWKRVKAKLE GRDVDPNRRM SVAEQVDYVI KEATNLDNLA QLYEGW TAW V

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Macromolecule #2: INOSITOL HEXAKISPHOSPHATE

MacromoleculeName: INOSITOL HEXAKISPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: IHP
Molecular weightTheoretical: 660.035 Da
Chemical component information

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE / Phytic acid

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Macromolecule #3: 1-[4-[4-[2-[[4-chloranyl-3-(diethylsulfamoyl)phenyl]amino]pyrimid...

MacromoleculeName: 1-[4-[4-[2-[[4-chloranyl-3-(diethylsulfamoyl)phenyl]amino]pyrimidin-4-yl]pyridin-2-yl]phenyl]-3-methyl-urea
type: ligand / ID: 3 / Number of copies: 1 / Formula: 88C
Molecular weightTheoretical: 566.074 Da
Chemical component information

ChemComp-88C:
1-[4-[4-[2-[[4-chloranyl-3-(diethylsulfamoyl)phenyl]amino]pyrimidin-4-yl]pyridin-2-yl]phenyl]-3-methyl-urea

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 89.32 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 228291

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