+Open data
-Basic information
Entry | Database: PDB / ID: 8djm | |||||||||
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Title | HMGCR-UBIAD1 Complex State 1 | |||||||||
Components |
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Keywords | Oxidoreductase/Immune System / Cholesterol / MEMBRANE PROTEIN / Oxidoreductase-Immune System complex | |||||||||
Function / homology | Function and homology information vitamin K biosynthetic process / : / hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / coenzyme A binding / negative regulation of amyloid-beta clearance / prenyltransferase activity / coenzyme A metabolic process / menaquinone biosynthetic process / ubiquinone biosynthetic process ...vitamin K biosynthetic process / : / hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / coenzyme A binding / negative regulation of amyloid-beta clearance / prenyltransferase activity / coenzyme A metabolic process / menaquinone biosynthetic process / ubiquinone biosynthetic process / isoprenoid biosynthetic process / peroxisomal membrane / cholesterol biosynthetic process / antioxidant activity / negative regulation of protein secretion / NADPH binding / negative regulation of MAP kinase activity / electron transport chain / visual learning / negative regulation of protein catabolic process / membrane => GO:0016020 / periplasmic space / electron transfer activity / iron ion binding / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum / nucleus Similarity search - Function | |||||||||
Biological species | Cricetulus griseus (Chinese hamster) Escherichia coli (E. coli) Mus musculus (house mouse) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.23 Å | |||||||||
Authors | Chen, H. / Qi, X. / Li, X. | |||||||||
Funding support | United States, 2items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8djm.cif.gz | 191.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8djm.ent.gz | 149.3 KB | Display | PDB format |
PDBx/mmJSON format | 8djm.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8djm_validation.pdf.gz | 1.7 MB | Display | wwPDB validaton report |
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Full document | 8djm_full_validation.pdf.gz | 1.7 MB | Display | |
Data in XML | 8djm_validation.xml.gz | 45.5 KB | Display | |
Data in CIF | 8djm_validation.cif.gz | 60.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/dj/8djm ftp://data.pdbj.org/pub/pdb/validation_reports/dj/8djm | HTTPS FTP |
-Related structure data
Related structure data | 27461MC 8djkC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 3 types, 3 molecules ABC
#1: Protein | Mass: 41215.859 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Cricetulus griseus (Chinese hamster) / Gene: HMGCR / Production host: Homo sapiens (human) References: UniProt: P00347, hydroxymethylglutaryl-CoA reductase (NADPH) |
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#2: Protein | Mass: 32780.508 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Cricetulus griseus (Chinese hamster) / Gene: Ubiad1, CgPICR_017873, H671_2g6271, I79_022097 / Production host: Homo sapiens (human) / References: UniProt: G3IEF0 |
#3: Protein | Mass: 13470.236 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Escherichia coli (E. coli) / Gene: cybC / Production host: Homo sapiens (human) / References: UniProt: P0ABE7 |
-Antibody , 2 types, 2 molecules LH
#4: Antibody | Mass: 23373.771 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human) |
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#5: Antibody | Mass: 25175.154 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human) |
-Non-polymers , 2 types, 8 molecules
#6: Chemical | ChemComp-Y01 / #7: Chemical | |
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-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component |
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Source (natural) | Organism: Cricetulus griseus (Chinese hamster) | ||||||||||||||||||
Source (recombinant) | Organism: Homo sapiens (human) | ||||||||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 8.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software | Name: REFMAC / Version: 5.8.0158 / Classification: refinement | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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CTF correction | Type: NONE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 215396 / Symmetry type: POINT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement | Resolution: 3.23→269.44 Å / Cor.coef. Fo:Fc: 0.799 / SU B: 14.987 / SU ML: 0.22 / ESU R: 0.116 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 139.858 Å2
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Refinement step | Cycle: 1 / Total: 7032 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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