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- EMDB-19757: CryoEM structure of Apo form of catalytic domain of human HMG-CoA... -

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Basic information

Entry
Database: EMDB / ID: EMD-19757
TitleCryoEM structure of Apo form of catalytic domain of human HMG-CoA reductase
Map dataFinal map from Relion and hand inverted
Sample
  • Complex: human HMGCoA catalytic domain reductase
    • Protein or peptide: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
Keywordsreductase / cholesterol biosynthesis / lipitor / atorvastatin / statins / OXIDOREDUCTASE
Function / homology
Function and homology information


hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / sterol biosynthetic process / GTPase regulator activity / coenzyme A binding / negative regulation of amyloid-beta clearance / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / coenzyme A metabolic process / isoprenoid biosynthetic process ...hydroxymethylglutaryl-CoA reductase (NADPH) / hydroxymethylglutaryl-CoA reductase (NADPH) activity / sterol biosynthetic process / GTPase regulator activity / coenzyme A binding / negative regulation of amyloid-beta clearance / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / coenzyme A metabolic process / isoprenoid biosynthetic process / peroxisomal membrane / cholesterol biosynthetic process / negative regulation of protein secretion / NADPH binding / regulation of ERK1 and ERK2 cascade / Activation of gene expression by SREBF (SREBP) / PPARA activates gene expression / visual learning / negative regulation of protein catabolic process / long-term synaptic potentiation / endoplasmic reticulum membrane / endoplasmic reticulum
Similarity search - Function
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, 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
Similarity search - Domain/homology
3-hydroxy-3-methylglutaryl-coenzyme A reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.06 Å
AuthorsManikandan K / Van Rooyen J
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Diamond Light Source United Kingdom
CitationJournal: Science / Year: 2001
Title: Structural mechanism for statin inhibition of HMG-CoA reductase.
Authors: E S Istvan / J Deisenhofer /
Abstract: HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar ...HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.
History
DepositionFeb 27, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19757.png

Downloads & links

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Map

FileDownload / File: emd_19757.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFinal map from Relion and hand inverted
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 240 pix.
= 222. Å		0.93 Å/pix.
x 240 pix.
= 222. Å		0.93 Å/pix.
x 240 pix.
= 222. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.925 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.009628126 - 0.033124793
Average (Standard dev.)0.000035605746 (±0.0012213293)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 222.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19757_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

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Additional map: Relion final map is sharpened by locSpiral

Fileemd_19757_additional_1.map
AnnotationRelion final map is sharpened by locSpiral
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: Half1 map from Relion and hand inverted

Fileemd_19757_half_map_1.map
AnnotationHalf1 map from Relion and hand inverted
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half2 map from Relion and hand inverted

Fileemd_19757_half_map_2.map
AnnotationHalf2 map from Relion and hand inverted
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human HMGCoA catalytic domain reductase

EntireName: human HMGCoA catalytic domain reductase
Components
  • Complex: human HMGCoA catalytic domain reductase
    • Protein or peptide: 3-hydroxy-3-methylglutaryl-coenzyme A reductase

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Supramolecule #1: human HMGCoA catalytic domain reductase

SupramoleculeName: human HMGCoA catalytic domain reductase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 240 KDa

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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: Homo sapiens (human)
Molecular weightTheoretical: 45.259016 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: PREPRPNEEC LQILGNAEKG AKFLSDAEII QLVNAKHIPA YKLETLMETH ERGVSIRRQL LSKKLSEPSS LQYLPYRDYN YSLVMGACC ENVIGYMPIP VGVAGPLCLD EKEFQVPMAT TEGCLVASTN RGCRAIGLGG GASSRVLADG MTRGPVVRLP R ACDSAEVK ...String:
PREPRPNEEC LQILGNAEKG AKFLSDAEII QLVNAKHIPA YKLETLMETH ERGVSIRRQL LSKKLSEPSS LQYLPYRDYN YSLVMGACC ENVIGYMPIP VGVAGPLCLD EKEFQVPMAT TEGCLVASTN RGCRAIGLGG GASSRVLADG MTRGPVVRLP R ACDSAEVK AWLETSEGFA VIKEAFDSTS RFARLQKLHT SIAGRNLYIR FQSRSGDAMG MNMISKGTEK ALSKLHEYFP EM QILAVSG NYCTDKKPAA INWIEGRGKS VVCEAVIPAK VVREVLKTTT EAMIEVNINK NLVGSAMAGS IGGYNAHAAN IVT AIYIAC GQDAAQNVGS SNCITLMEAS GPTNEDLYIS CTMPSIEIGT VGGGTNLLPQ QACLQMLGVQ GACKDNPGEN ARQL ARIVC GTVMAGELSL MAALAAGH

UniProtKB: 3-hydroxy-3-methylglutaryl-coenzyme A reductase

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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
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: GRAPHENE OXIDE / Support film - topology: CONTINUOUS / Support film - Film thickness: 0.3
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 13644 / Average electron dose: 54.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

DetailsFalcon4i
Particle selectionNumber selected: 5498554
Startup modelType of model: OTHER / Details: Model generated from data itself
Final reconstructionApplied symmetry - Point group: D2 (2x2 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 2.06 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5) / Number images used: 1066707
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5)
Final 3D classificationSoftware - Name: RELION (ver. 5)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

1hwk


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8s6b:
CryoEM structure of Apo form of catalytic domain of human HMG-CoA reductase

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