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- EMDB-24179: Structure of cholesterol-bound human NPC1L1 -

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Basic information

Entry
Database: EMDB / ID: EMD-24179
TitleStructure of cholesterol-bound human NPC1L1
Map dataStructure of cholesterol-bound human NPC1L1
Sample
  • Organelle or cellular component: Human NPC1L1 supplemented with cholesterol
    • Protein or peptide: Isoform 2 of NPC1-like intracellular cholesterol transporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
Function / homology
Function and homology information


Intestinal lipid absorption / cellular response to sterol depletion / vitamin E binding / vitamin E metabolic process / vitamin transport / intestinal cholesterol absorption / lipoprotein metabolic process / myosin V binding / cholesterol transport / cholesterol binding ...Intestinal lipid absorption / cellular response to sterol depletion / vitamin E binding / vitamin E metabolic process / vitamin transport / intestinal cholesterol absorption / lipoprotein metabolic process / myosin V binding / cholesterol transport / cholesterol binding / cholesterol biosynthetic process / cholesterol homeostasis / cytoplasmic vesicle membrane / small GTPase binding / apical plasma membrane / protein homodimerization activity / plasma membrane
Similarity search - Function
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
AuthorsLi X / Long T
CitationJournal: Sci Adv / Year: 2021
Title: Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption.
Authors: Tao Long / Yang Liu / Yu Qin / Russell A DeBose-Boyd / Xiaochun Li /
Abstract: Polytopic Niemann-Pick C1-like 1 (NPC1L1) plays a major role in intestinal absorption of biliary cholesterol, vitamin E (VE), and vitamin K (VK). The drug ezetimibe inhibits NPC1L1-mediated ...Polytopic Niemann-Pick C1-like 1 (NPC1L1) plays a major role in intestinal absorption of biliary cholesterol, vitamin E (VE), and vitamin K (VK). The drug ezetimibe inhibits NPC1L1-mediated absorption of cholesterol, lowering of circulating levels of low-density lipoprotein cholesterol. Here, we report cryo-electron microscopy structures of human NPC1L1 (hNPC1L1) bound to either cholesterol or a lipid resembling VE. These findings, together with functional assays, reveal that the same intramolecular channel in hNPC1L1 mediates transport of VE and cholesterol. hNPC1L1 exists primarily as a homodimer; dimerization is mediated by aromatic residues within a region of transmembrane helix 2 that exhibits a horizonal orientation in the membrane. Mutation of tryptophan-347 lies in this region disrupts dimerization and the resultant monomeric NPC1L1 exhibits reduced efficiency of cholesterol uptake. These findings identify the oligomeric state of hNPC1L1 as a target for therapies that inhibit uptake of dietary cholesterol and reduce the incidence of cardiovascular disease.
History
DepositionJun 4, 2021-
Header (metadata) releaseSep 1, 2021-
Map releaseSep 1, 2021-
UpdateMar 16, 2022-
Current statusMar 16, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.246
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.246
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7n4v
  • Surface level: 0.246
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24179.png

Downloads & links

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Map

FileDownload / File: emd_24179.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of cholesterol-bound human NPC1L1
Voxel sizeX=Y=Z: 0.833 Å
Density
Contour LevelBy AUTHOR: 0.246 / Movie #1: 0.246
Minimum - Maximum-1.2329344 - 2.3408146
Average (Standard dev.)0.0048998278 (±0.04467222)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 299.88 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8330.8330.833
M x/y/z360360360
origin x/y/z0.0000.0000.000
length x/y/z299.880299.880299.880
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS360360360
D min/max/mean-1.2332.3410.005

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Supplemental data

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Sample components

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Entire : Human NPC1L1 supplemented with cholesterol

EntireName: Human NPC1L1 supplemented with cholesterol
Components
  • Organelle or cellular component: Human NPC1L1 supplemented with cholesterol
    • Protein or peptide: Isoform 2 of NPC1-like intracellular cholesterol transporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate

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Supramolecule #1: Human NPC1L1 supplemented with cholesterol

SupramoleculeName: Human NPC1L1 supplemented with cholesterol / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Isoform 2 of NPC1-like intracellular cholesterol transporter 1

MacromoleculeName: Isoform 2 of NPC1-like intracellular cholesterol transporter 1
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 145.904031 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 DGQVLTS RFMAYHKPLK NSQDYTEALR AARELAANIT ADLRKVPGTD PAFEVFPYTI TNVFYEQYLT ILPEGLFMLS LCL VPTFAV SCLLLGLDLR SGLLNLLSIV MILVDTVGFM ALWGISYNAV SLINLVSAVG MSVEFVSHIT RSFAISTKPT WLER AKEAT ISMGSAVFAG VAMTNLPGIL VLGLAKAQLI QIFFFRLNLL ITLLGLLHGL VFLPVILSYV GPDVNPALAL EQKRA EEAV AAVMVASCPN HPSRVSTADN IYVNHSFEGS IKGAGAISNF LPNNGRQF

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 8 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 6 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #5: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 5 / Number of copies: 2 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 251678

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