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- EMDB-30667: delta N-NPC1L1 in the apo state -

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Basic information

Entry
Database: EMDB / ID: EMD-30667
Titledelta N-NPC1L1 in the apo state
Map data
Sample
  • Cell: membrane protein delta N-NPC1L1 in the apo state
Function / homology
Function and homology information


vitamin transport / cholesterol import / lipid transporter activity / heterocyclic compound binding / response to muscle activity / endomembrane system / cholesterol metabolic process / brush border membrane / apical plasma membrane / response to xenobiotic stimulus
Similarity search - Function
NPC1-like / Niemann-Pick C1, N-terminal / : / Niemann-Pick C1 N terminus / NPC1, middle luminal domain / : / Sterol-sensing domain of SREBP cleavage-activation / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain
Similarity search - Domain/homology
NPC1 like intracellular cholesterol transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsHu M / Sun S
CitationJournal: Sci Adv / Year: 2021
Title: Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake.
Authors: Miaoqing Hu / Fan Yang / Yawen Huang / Xin You / Desheng Liu / Shan Sun / Sen-Fang Sui /
Abstract: Niemann-Pick C1-like 1 (NPC1L1) protein plays a central role in the intestinal cholesterol absorption and is the target of a drug, ezetimibe, which inhibits NPC1L1 to reduce cholesterol absorption. ...Niemann-Pick C1-like 1 (NPC1L1) protein plays a central role in the intestinal cholesterol absorption and is the target of a drug, ezetimibe, which inhibits NPC1L1 to reduce cholesterol absorption. Here, we present cryo-electron microscopy structures of human NPC1L1 in apo state, cholesterol-enriched state, and ezetimibe-bound state to reveal molecular details of NPC1L1-mediated cholesterol uptake and ezetimibe inhibition. Comparison of these structures reveals that the sterol-sensing domain (SSD) could respond to the cholesterol level alteration by binding different number of cholesterol molecules. Upon increasing cholesterol level, SSD binds more cholesterol molecules, which, in turn, triggers the formation of a stable structural cluster in SSD, while binding of ezetimibe causes the deformation of the SSD and destroys the structural cluster, leading to the inhibition of NPC1L1 function. These results provide insights into mechanisms of NPC1L1 function and ezetimibe action and are of great significance for the development of new cholesterol absorption inhibitors.
History
DepositionNov 10, 2020-
Header (metadata) releaseAug 4, 2021-
Map releaseAug 4, 2021-
UpdateAug 4, 2021-
Current statusAug 4, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0736
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.0736
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30667.png

Downloads & links

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Map

FileDownload / File: emd_30667.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 320 pix.
= 339.52 Å		1.06 Å/pix.
x 320 pix.
= 339.52 Å		1.06 Å/pix.
x 320 pix.
= 339.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.061 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0736 / Movie #1: 0.0736
Minimum - Maximum-0.29569054 - 0.35098568
Average (Standard dev.)7.990863e-05 (±0.00663763)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 339.52 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0611.0611.061
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z339.520339.520339.520
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.2960.3510.000

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Supplemental data

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Sample components

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Entire : membrane protein delta N-NPC1L1 in the apo state

EntireName: membrane protein delta N-NPC1L1 in the apo state
Components
  • Cell: membrane protein delta N-NPC1L1 in the apo state

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Supramolecule #1: membrane protein delta N-NPC1L1 in the apo state

SupramoleculeName: membrane protein delta N-NPC1L1 in the apo state / type: cell / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2164284
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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