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- EMDB-27460: HMGCR-UBIAD1 Complex Dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-27460
TitleHMGCR-UBIAD1 Complex Dimer
Map dataHMGCR-UBIAD1 Complex State 2
Sample
  • Complex: HMGCR-UBIAD1-BRIL-Fab 15B2 complex
    • Complex: HMGCR-UBIAD1-BRIL-Fab 15B2 complex
      • Protein or peptide: 3-hydroxy-3-methylglutaryl-coenzyme A reductaseHMG-CoA reductase
      • Protein or peptide: UbiA prenyltransferase domain-containing protein 1
      • Protein or peptide: Soluble cytochrome b562
      • Protein or peptide: Fab 15B2 Light Chain
      • Protein or peptide: Fab 15B2 Heavy Chain
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: Digitonin
Function / homology
Function and homology information


vitamin K biosynthetic process / : / hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / ubiquinone biosynthetic process / coenzyme A binding / negative regulation of amyloid-beta clearance / prenyltransferase activity / menaquinone biosynthetic process / coenzyme A metabolic process ...vitamin K biosynthetic process / : / hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / ubiquinone biosynthetic process / coenzyme A binding / negative regulation of amyloid-beta clearance / prenyltransferase activity / menaquinone biosynthetic process / coenzyme A metabolic process / peroxisomal membrane / isoprenoid biosynthetic process / antioxidant activity / cholesterol biosynthetic process / negative regulation of protein secretion / NADPH binding / negative regulation of MAP kinase activity / visual learning / negative regulation of protein catabolic process / electron transfer activity / membrane => GO:0016020 / periplasmic space / iron ion binding / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum / nucleus
Similarity search - Function
UbiA prenyltransferase domain containing protein 1 / UbiA prenyltransferase family / UbiA prenyltransferase superfamily / UbiA prenyltransferase family / Hydroxymethylglutaryl-CoA reductase, metazoan / Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type / Hydroxymethylglutaryl-CoA reductase, N-terminal / Hydroxymethylglutaryl-coenzyme A reductases signature 2. / Hydroxymethylglutaryl-coenzyme A reductases signature 1. / Hydroxymethylglutaryl-coenzyme A reductases signature 3. ...UbiA prenyltransferase domain containing protein 1 / UbiA prenyltransferase family / UbiA prenyltransferase superfamily / UbiA prenyltransferase family / Hydroxymethylglutaryl-CoA reductase, metazoan / Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type / Hydroxymethylglutaryl-CoA reductase, N-terminal / Hydroxymethylglutaryl-coenzyme A reductases signature 2. / Hydroxymethylglutaryl-coenzyme A reductases signature 1. / Hydroxymethylglutaryl-coenzyme A reductases signature 3. / Hydroxymethylglutaryl-CoA reductase, class I/II / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain superfamily / Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain superfamily / Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain superfamily / Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site / Hydroxymethylglutaryl-coenzyme A reductase / Hydroxymethylglutaryl-coenzyme A reductases family profile. / Sterol-sensing domain of SREBP cleavage-activation / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562
Similarity search - Domain/homology
UbiA prenyltransferase domain-containing protein 1 / 3-hydroxy-3-methylglutaryl-coenzyme A reductase / Soluble cytochrome b562
Similarity search - Component
Biological speciesCricetulus griseus (Chinese hamster) / Escherichia coli (E. coli) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.33 Å
AuthorsChen H / Qi X / Li X
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
Welch Foundation United States
CitationJournal: Nat Commun / Year: 2022
Title: Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain.
Authors: Hongwen Chen / Xiaofeng Qi / Rebecca A Faulkner / Marc M Schumacher / Linda M Donnelly / Russell A DeBose-Boyd / Xiaochun Li /
Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme in cholesterol synthesis and target of cholesterol-lowering statin drugs. Accumulation of sterols in endoplasmic ...3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme in cholesterol synthesis and target of cholesterol-lowering statin drugs. Accumulation of sterols in endoplasmic reticulum (ER) membranes accelerates degradation of HMGCR, slowing the synthesis of cholesterol. Degradation of HMGCR is inhibited by its binding to UBIAD1 (UbiA prenyltransferase domain-containing protein-1). This inhibition contributes to statin-induced accumulation of HMGCR, which limits their cholesterol-lowering effects. Here, we report cryo-electron microscopy structures of the HMGCR-UBIAD1 complex, which is maintained by interactions between transmembrane helix (TM) 7 of HMGCR and TMs 2-4 of UBIAD1. Disrupting this interface by mutagenesis prevents complex formation, enhancing HMGCR degradation. TMs 2-6 of HMGCR contain a 170-amino acid sterol sensing domain (SSD), which exists in two conformations-one of which is essential for degradation. Thus, our data supports a model that rearrangement of the TMs in the SSD permits recruitment of proteins that initate HMGCR degradation, a key reaction in the regulatory system that governs cholesterol synthesis.
History
DepositionJun 30, 2022-
Header (metadata) releaseAug 3, 2022-
Map releaseAug 3, 2022-
UpdateAug 3, 2022-
Current statusAug 3, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27460.png

Downloads & links

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Map

FileDownload / File: emd_27460.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHMGCR-UBIAD1 Complex State 2
Voxel sizeX=Y=Z: 0.842 Å
Density
Contour LevelBy AUTHOR: 0.351
Minimum - Maximum-3.2956293 - 4.993014
Average (Standard dev.)0.0026787734 (±0.07979339)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 269.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_27460_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_27460_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : HMGCR-UBIAD1-BRIL-Fab 15B2 complex

EntireName: HMGCR-UBIAD1-BRIL-Fab 15B2 complex
Components
  • Complex: HMGCR-UBIAD1-BRIL-Fab 15B2 complex
    • Complex: HMGCR-UBIAD1-BRIL-Fab 15B2 complex
      • Protein or peptide: 3-hydroxy-3-methylglutaryl-coenzyme A reductaseHMG-CoA reductase
      • Protein or peptide: UbiA prenyltransferase domain-containing protein 1
      • Protein or peptide: Soluble cytochrome b562
      • Protein or peptide: Fab 15B2 Light Chain
      • Protein or peptide: Fab 15B2 Heavy Chain
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: Digitonin

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Supramolecule #1: HMGCR-UBIAD1-BRIL-Fab 15B2 complex

SupramoleculeName: HMGCR-UBIAD1-BRIL-Fab 15B2 complex / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#5

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Supramolecule #2: HMGCR-UBIAD1-BRIL-Fab 15B2 complex

SupramoleculeName: HMGCR-UBIAD1-BRIL-Fab 15B2 complex / type: complex / Chimera: Yes / ID: 2 / Parent: 1 / Macromolecule list: #1-#5
Source (natural)Organism: Cricetulus griseus (Chinese hamster)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: 3-hydroxy-3-methylglutaryl-coenzyme A reductase

MacromoleculeName: 3-hydroxy-3-methylglutaryl-coenzyme A reductase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: hydroxymethylglutaryl-CoA reductase (NADPH)
Source (natural)Organism: Cricetulus griseus (Chinese hamster)
Molecular weightTheoretical: 41.215859 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKL SRLFRMHGLF VASHPWEVIV GTVTLTICMM SMNMFTGNNK ICGWNYECPK FEEDVLSSDI IILTITRCIA ILYIYFQFQ NLRQLGSRYI LGIAGLFTIF SSFVFSTVVI HFLDKELTGL NEALPFFLLL IDLSRASALA KFALSSNSQD E VRENIARG ...String:
MDYKDDDDKL SRLFRMHGLF VASHPWEVIV GTVTLTICMM SMNMFTGNNK ICGWNYECPK FEEDVLSSDI IILTITRCIA ILYIYFQFQ NLRQLGSRYI LGIAGLFTIF SSFVFSTVVI HFLDKELTGL NEALPFFLLL IDLSRASALA KFALSSNSQD E VRENIARG MAILGPTFTL DALVECLVIG VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PI WQLSHFA RVLEEEENRP NPVTQRVKMI MSLGLVLVHA HSRWIADPSP QNSTTEHSKV SLGLDEDVSK RIEPSVSLWQ FYL SKMISM DIEQVVTLSL AFLLAVKYIF FEQAETESTL SLKNPITS

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Macromolecule #2: UbiA prenyltransferase domain-containing protein 1

MacromoleculeName: UbiA prenyltransferase domain-containing protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Cricetulus griseus (Chinese hamster)
Molecular weightTheoretical: 32.780508 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASSWRQKCA SYVLALRPWS FSASLTPVAL GSALAYRSQG VLDPRLLVGC AVAVLAVHGA GNLVSTYYDF SKGIDHKKSD DRTLVDRIL EPQDVVRFGV FLYTLGCVCA ACLYYLSTLK LEHLALIYFG GLSGSFLYTG GIGFKYVALG DLIILITFGP L AVMFAYAV ...String:
MASSWRQKCA SYVLALRPWS FSASLTPVAL GSALAYRSQG VLDPRLLVGC AVAVLAVHGA GNLVSTYYDF SKGIDHKKSD DRTLVDRIL EPQDVVRFGV FLYTLGCVCA ACLYYLSTLK LEHLALIYFG GLSGSFLYTG GIGFKYVALG DLIILITFGP L AVMFAYAV QVGSLAIFPL VYAIPLALST EAILHSNNTR DMESDQEAGI VTLAILIGPT FSYVLYNTLL FLPYLIFSIL AT HCSISLA LPLLTIPMAF SLERQFRSQA FNKLPQRTAK LNLLLGLFYV FGIILAPAGS LPRL

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Macromolecule #3: Soluble cytochrome b562

MacromoleculeName: Soluble cytochrome b562 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 13.470236 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
ARRLALEDNW ETLNDNLKVI EKADNAAQVK DALTKMRAAA LDAQKATPPK LEDKSPDSPE MKDFRHGFDI LVGQIDDALK LANEGKVKE AQAAAEQLKT TRNAYIQKYL ERARSTLQKE V

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Macromolecule #4: Fab 15B2 Light Chain

MacromoleculeName: Fab 15B2 Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.373771 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DILLTQSPAI LSVSPGERVS FSCRASQSIG TSIHWYQQRT NGSPRLVIKY ASESISGIPS RFSGSGSGTD FTLSINSVES EDIADYYCQ QSNSWPYTFG GGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DILLTQSPAI LSVSPGERVS FSCRASQSIG TSIHWYQQRT NGSPRLVIKY ASESISGIPS RFSGSGSGTD FTLSINSVES EDIADYYCQ QSNSWPYTFG GGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #5: Fab 15B2 Heavy Chain

MacromoleculeName: Fab 15B2 Heavy Chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 25.175154 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLQQSGPE LVKPGASVKM SCKASGYSFT GYFMNWVKQS HGKSLEWIGR INPYNGDTFY NQKFKGKATL TVDKSSRTAH MELRSLTSA DSALYFCVRR GEDYGSSYNY WGQGTTVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
EVQLQQSGPE LVKPGASVKM SCKASGYSFT GYFMNWVKQS HGKSLEWIGR INPYNGDTFY NQKFKGKATL TVDKSSRTAH MELRSLTSA DSALYFCVRR GEDYGSSYNY WGQGTTVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EPKSCDKTHH HHHH

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Macromolecule #6: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 6 / Number of copies: 6 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #7: Digitonin

MacromoleculeName: Digitonin / type: ligand / ID: 7 / Number of copies: 2 / Formula: AJP
Molecular weightTheoretical: 1.229312 KDa
Chemical component information

ChemComp-AJP:
Digitonin / detergent*YM / Digitonin

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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: 7.5
VitrificationCryogen name: ETHANE

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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 / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 8.5 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.33 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 285496

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