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- PDB-8djk: HMGCR-UBIAD1 Complex State 2 -

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Basic information

Entry
Database: PDB / ID: 8djk
TitleHMGCR-UBIAD1 Complex State 2
Components
  • 3-hydroxy-3-methylglutaryl-coenzyme A reductaseHMG-CoA reductase
  • Fab 15B2 Heavy Chain
  • Fab 15B2 Light Chain
  • Soluble cytochrome b562
  • UbiA prenyltransferase domain-containing protein 1
KeywordsOxidoreductase/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 / 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
CHOLESTEROL HEMISUCCINATE / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.33 Å
AuthorsChen, H. / Qi, X. / Li, X.
Funding support United States, 2items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
B: UbiA prenyltransferase domain-containing protein 1
C: Soluble cytochrome b562
L: Fab 15B2 Light Chain
H: Fab 15B2 Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,39513
Polymers136,0165
Non-polymers5,3798
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein 3-hydroxy-3-methylglutaryl-coenzyme A reductase / HMG-CoA reductase / HMG-CoA reductase


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)
#2: Protein UbiA prenyltransferase domain-containing protein 1


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 Soluble cytochrome b562 / Cytochrome b-562


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

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Antibody , 2 types, 2 molecules LH

#4: Antibody Fab 15B2 Light Chain


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)
#5: Antibody Fab 15B2 Heavy Chain


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)

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Non-polymers , 2 types, 8 molecules

#6: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C31H50O4
#7: Chemical ChemComp-AJP / Digitonin / Digitonin


Mass: 1229.312 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C56H92O29 / Comment: detergent*YM

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1HMGCR-UBIAD1-BRIL-Fab 15B2 complexCOMPLEX#1-#50RECOMBINANT
2HMGCR-UBIAD1-BRIL-Fab 15B2 complexCOMPLEX#1-#51RECOMBINANT
Source (natural)Organism: Cricetulus griseus (Chinese hamster)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 8.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0158 / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.33 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 285496 / Symmetry type: POINT
RefinementResolution: 3.33→269.44 Å / Cor.coef. Fo:Fc: 0.762 / SU B: 17.02 / SU ML: 0.251 / ESU R: 0.131 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.48727 --
obs0.48727 1109317 100 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 124.558 Å2
Baniso -1Baniso -2Baniso -3
1--1.49 Å21.38 Å2-2.17 Å2
2--1.14 Å21.02 Å2
3---0.35 Å2
Refinement stepCycle: 1 / Total: 7091
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0080.0197267
ELECTRON MICROSCOPYr_bond_other_d0.0060.026947
ELECTRON MICROSCOPYr_angle_refined_deg1.4012.0239915
ELECTRON MICROSCOPYr_angle_other_deg1.01316111
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.4365860
ELECTRON MICROSCOPYr_dihedral_angle_2_deg33.31923.273278
ELECTRON MICROSCOPYr_dihedral_angle_3_deg14.345151161
ELECTRON MICROSCOPYr_dihedral_angle_4_deg15.5481540
ELECTRON MICROSCOPYr_chiral_restr0.0840.21185
ELECTRON MICROSCOPYr_gen_planes_refined0.0060.027630
ELECTRON MICROSCOPYr_gen_planes_other0.0010.021458
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it1.71812.7583470
ELECTRON MICROSCOPYr_mcbond_other1.71812.7593469
ELECTRON MICROSCOPYr_mcangle_it3.29219.1184320
ELECTRON MICROSCOPYr_mcangle_other3.29219.1174321
ELECTRON MICROSCOPYr_scbond_it0.94112.7883797
ELECTRON MICROSCOPYr_scbond_other0.94112.7873796
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other1.94619.1025596
ELECTRON MICROSCOPYr_long_range_B_refined7.5468295
ELECTRON MICROSCOPYr_long_range_B_other7.5458296
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.33→3.417 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rwork2.807 82393 -
Rfree-0 -
obs--100 %

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