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- EMDB-30668: Cryo_EM structure of delta N-NPC1L1-EZE -

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Basic information

Entry
Database: EMDB / ID: EMD-30668
TitleCryo_EM structure of delta N-NPC1L1-EZE
Map data
Sample
  • Complex: delta N-hNPC1L1-EZE
    • Protein or peptide: NPC1-like intracellular cholesterol transporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3~{R},4~{S})-1-(4-fluorophenyl)-3-[(3~{S})-3-(4-fluorophenyl)-3-oxidanyl-propyl]-4-(4-hydroxyphenyl)azetidin-2-one
  • Ligand: CHOLESTEROL
Function / homology
Function and homology information


vitamin transport / cholesterol import / intestinal cholesterol absorption / lipid transporter activity / response to muscle activity / heterocyclic compound binding / cholesterol binding / cholesterol homeostasis / brush border membrane / response to xenobiotic stimulus / apical plasma membrane
Similarity search - Function
NPC1-like / Niemann-Pick C1, N-terminal / Niemann-Pick C1 N terminus / Sterol-sensing domain of SREBP cleavage-activation / Protein patched/dispatched / Patched family / 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: 3.58 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 11, 2021-
Map releaseAug 11, 2021-
UpdateAug 11, 2021-
Current statusAug 11, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0783
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.0783
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dfz
  • Surface level: 0.0783
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30668.png

Downloads & links

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Map

FileDownload / File: emd_30668.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.091 Å
Density
Contour LevelBy AUTHOR: 0.0783 / Movie #1: 0.0783
Minimum - Maximum-0.32197618 - 0.5173438
Average (Standard dev.)0.00017912334 (±0.007506673)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 349.12 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0911.0911.091
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z349.120349.120349.120
α/β/γ90.00090.00090.000
start NX/NY/NZ594743
NX/NY/NZ375263
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.3220.5170.000

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Supplemental data

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Sample components

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Entire : delta N-hNPC1L1-EZE

EntireName: delta N-hNPC1L1-EZE
Components
  • Complex: delta N-hNPC1L1-EZE
    • Protein or peptide: NPC1-like intracellular cholesterol transporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3~{R},4~{S})-1-(4-fluorophenyl)-3-[(3~{S})-3-(4-fluorophenyl)-3-oxidanyl-propyl]-4-(4-hydroxyphenyl)azetidin-2-one
  • Ligand: CHOLESTEROL

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Supramolecule #1: delta N-hNPC1L1-EZE

SupramoleculeName: delta N-hNPC1L1-EZE / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293

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Macromolecule #1: NPC1-like intracellular cholesterol transporter 1

MacromoleculeName: NPC1-like intracellular cholesterol transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 139.612125 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAEAGLRGWL LWALLLRLAQ SEPYTTIHQP GYCAFYDECG KNPELSGSLM TLSNVSCLSN TPARKITGDH LILLQKICPR LYTGPNTQA CCSAKQLVSL EASLSITKAL LTRCPACSDN FVNLHCHNTC SPNQSLFINV TRVAQLGAGQ LPAVVAYEAF Y QHSFAEQS ...String:
MAEAGLRGWL LWALLLRLAQ SEPYTTIHQP GYCAFYDECG KNPELSGSLM TLSNVSCLSN TPARKITGDH LILLQKICPR LYTGPNTQA CCSAKQLVSL EASLSITKAL LTRCPACSDN FVNLHCHNTC SPNQSLFINV TRVAQLGAGQ LPAVVAYEAF Y QHSFAEQS YDSCSRVRVP AAATLAVGTM CGVYGSALCN AQRWLNFQGD TGNGLAPLDI TFHLLEPGQA VGSGIQPLNE GV ARCNESQ GDDVATCSCQ DCAASCPAIA RPQALDSTFY LGQMPGSLVL IIILCSVFAV VTILLVGFRV APARDKSKMV DPK KGTSLS DKLSFSTHTL LGQFFQGWGT WVASWPLTIL VLSVIPVVAL AAGLVFTELT TDPVELWSAP NSQARSEKAF HDQH FGPFF RTNQVILTAP NRSSYRYDSL LLGPKNFSGI LDLDLLLELL ELQERLRHLQ VWSPEAQRNI SLQDICYAPL NPDNT SLYD CCINSLLQYF QNNRTLLLLT ANQTLMGQTS QVDWKDHFLY CANAPLTFKD GTALALSCMA DYGAPVFPFL AIGGYK GKD YSEAEALIMT FSLNNYPAGD PRLAQAKLWE EAFLEEMRAF QRRMAGMFQV TFMAERSLED EINRTTAEDL PIFATSY IV IFLYISLALG SYSSWSRVMV DSKATLGLGG VAVVLGAVMA AMGFFSYLGI RSSLVILQVV PFLVLSVGAD NIFIFVLE Y QRLPRRPGEP REVHIGRALG RVAPSMLLCS LSEAICFFLG ALTPMPAVRT FALTSGLAVI LDFLLQMSAF VALLSLDSK RQEASRLDVC CCVKPQELPP PGQGEGLLLG FFQKAYAPFL LHWITRGVVL LLFLALFGVS LYSMCHISVG LDQELALPKD SYLLDYFLF LNRYFEVGAP VYFVTTLGYN FSSEAGMNAI CSSAGCNNFS FTQKIQYATE FPEQSYLAIP ASSWVDDFID W LTPSSCCR LYISGPNKDK FCPSTVNSLN CLKNCMSITM GSVRPSVEQF HKYLPWFLND RPNIKCPKGG LAAYSTSVNL TS DGQVLAS RFMAYHKPLK NSQDYTEALR AARELAANIT ADLRKVPGTD PAFEVFPYTI TNVFYEQYLT ILPEGLFMLS LCL VPTFAV SCLLLGLDLR SGLLNLLSIV MILVDTVGFM ALWGISYNAV SLINLVSAVG MSVEFVSHIT RSFAISTKPT WLER AKEAT ISMGSAVFAG VAMTNLPGIL VLGLAKAQLI QIFFFRLNLL ITLLGLLHGL VFLPVILSYV GPDVNPAL

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #6: (3~{R},4~{S})-1-(4-fluorophenyl)-3-[(3~{S})-3-(4-fluorophenyl)-3-...

MacromoleculeName: (3~{R},4~{S})-1-(4-fluorophenyl)-3-[(3~{S})-3-(4-fluorophenyl)-3-oxidanyl-propyl]-4-(4-hydroxyphenyl)azetidin-2-one
type: ligand / ID: 6 / Number of copies: 1 / Formula: H56
Molecular weightTheoretical: 409.425 Da
Chemical component information

ChemComp-H56:
(3~{R},4~{S})-1-(4-fluorophenyl)-3-[(3~{S})-3-(4-fluorophenyl)-3-oxidanyl-propyl]-4-(4-hydroxyphenyl)azetidin-2-one / medication*YM

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Macromolecule #7: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2204129
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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