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- EMDB-17748: CryoEM structure of catalytic domain of human HMG-CoA reductase w... -

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Basic information

Entry
Database: EMDB / ID: EMD-17748
TitleCryoEM structure of catalytic domain of human HMG-CoA reductase with its inhibitor atorvastatin
Map dataThe final map at the end of refinement
Sample
  • Complex: Catalytic part of hHMGCoA reductase
    • Protein or peptide: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
  • Ligand: 7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID
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: 2.26 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
DepositionJun 27, 2023-
Header (metadata) releaseJan 15, 2025-
Map releaseJan 15, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17748.png

Downloads & links

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Map

FileDownload / File: emd_17748.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe final map at the end of refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 240 pix.
= 199.2 Å		0.83 Å/pix.
x 240 pix.
= 199.2 Å		0.83 Å/pix.
x 240 pix.
= 199.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.006058449 - 0.023691216
Average (Standard dev.)0.00004548451 (±0.0012037753)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 199.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_17748_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpend map using locspiral program

Fileemd_17748_additional_1.map
AnnotationSharpend map using locspiral program
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_17748_half_map_1.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_17748_half_map_2.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Catalytic part of hHMGCoA reductase

EntireName: Catalytic part of hHMGCoA reductase
Components
  • Complex: Catalytic part of hHMGCoA reductase
    • Protein or peptide: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
  • Ligand: 7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID

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Supramolecule #1: Catalytic part of hHMGCoA reductase

SupramoleculeName: Catalytic part of hHMGCoA reductase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 214 kDa/nm

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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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Macromolecule #2: 7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYR...

MacromoleculeName: 7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID
type: ligand / ID: 2 / Number of copies: 1 / Formula: 117
Molecular weightTheoretical: 558.64 Da
Chemical component information

ChemComp-117:
7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID / medication*YM

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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: 0.5
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 18337 / Average electron dose: 42.0 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 / Nominal magnification: 105000
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

Particle selectionNumber selected: 3061130
Startup modelType of model: OTHER / Details: Initial model generated from data itself
Final reconstructionApplied symmetry - Point group: D2 (2x2 fold dihedral) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 2.26 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 404712
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.0)
Final 3D classificationNumber classes: 3 / Software - Name: RELION (ver. 4.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

1hwk


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8pkn:
CryoEM structure of catalytic domain of human HMG-CoA reductase with its inhibitor atorvastatin

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