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- EMDB-21035: Structure of NPC1-like intracellular cholesterol transporter 1 (N... -

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Basic information

Entry
Database: EMDB / ID: EMD-21035
TitleStructure of NPC1-like intracellular cholesterol transporter 1 (NPC1L1)
Map dataStructure of full-length NPC1L1
Sample
  • Organelle or cellular component: NPC1-like intracellular cholesterol transporter 1 (NPC1L1)
    • Protein or peptide: NPC1-like intracellular cholesterol transporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
Function / homology
Function and homology information


Intestinal lipid absorption / cellular response to sterol depletion / vitamin E binding / vitamin E metabolic process / sterol transport / sterol binding / vitamin transport / cholesterol import / intestinal cholesterol absorption / lipid transporter activity ...Intestinal lipid absorption / cellular response to sterol depletion / vitamin E binding / vitamin E metabolic process / sterol transport / sterol binding / vitamin transport / cholesterol import / intestinal cholesterol absorption / lipid transporter activity / lipoprotein metabolic process / myosin V binding / cholesterol transport / response to muscle activity / heterocyclic compound binding / cholesterol binding / cholesterol biosynthetic process / cholesterol homeostasis / brush border membrane / small GTPase binding / response to xenobiotic stimulus / apical plasma membrane / protein homodimerization activity / membrane / 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 speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsHuang CS / Yu X / Min X / Wang Z
CitationJournal: Sci Adv / Year: 2020
Title: Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition.
Authors: Ching-Shin Huang / Xinchao Yu / Preston Fordstrom / Kaylee Choi / Ben C Chung / Soung-Hun Roh / Wah Chiu / Mingyue Zhou / Xiaoshan Min / Zhulun Wang /
Abstract: The intestinal absorption of cholesterol is mediated by a multipass membrane protein, Niemann-Pick C1-Like 1 (NPC1L1), the molecular target of a cholesterol lowering therapy ezetimibe. While ...The intestinal absorption of cholesterol is mediated by a multipass membrane protein, Niemann-Pick C1-Like 1 (NPC1L1), the molecular target of a cholesterol lowering therapy ezetimibe. While ezetimibe gained Food and Drug Administration approval in 2002, its mechanism of action has remained unclear. Here, we present two cryo-electron microscopy structures of NPC1L1, one in its apo form and the other complexed with ezetimibe. The apo form represents an open state in which the N-terminal domain (NTD) interacts loosely with the rest of NPC1L1, leaving the NTD central cavity accessible for cholesterol loading. The ezetimibe-bound form signifies a closed state in which the NTD rotates ~60°, creating a continuous tunnel enabling cholesterol movement into the plasma membrane. Ezetimibe blocks cholesterol transport by occluding the tunnel instead of competing with cholesterol binding. These findings provide insight into the molecular mechanisms of NPC1L1-mediated cholesterol transport and ezetimibe inhibition, paving the way for more effective therapeutic development.
History
DepositionNov 25, 2019-
Header (metadata) releaseJan 29, 2020-
Map releaseJul 1, 2020-
UpdateJul 29, 2020-
Current statusJul 29, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.011
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.011
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6v3f
  • Surface level: 0.011
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21035.png

Downloads & links

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Map

FileDownload / File: emd_21035.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of full-length NPC1L1
Voxel sizeX=Y=Z: 0.862 Å
Density
Contour LevelBy AUTHOR: 0.011 / Movie #1: 0.011
Minimum - Maximum-0.03853866 - 0.074918784
Average (Standard dev.)0.00008924439 (±0.002086216)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 275.84 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8620.8620.862
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z275.840275.840275.840
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0390.0750.000

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Supplemental data

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Sample components

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Entire : NPC1-like intracellular cholesterol transporter 1 (NPC1L1)

EntireName: NPC1-like intracellular cholesterol transporter 1 (NPC1L1)
Components
  • Organelle or cellular component: NPC1-like intracellular cholesterol transporter 1 (NPC1L1)
    • Protein or peptide: NPC1-like intracellular cholesterol transporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL

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Supramolecule #1: NPC1-like intracellular cholesterol transporter 1 (NPC1L1)

SupramoleculeName: NPC1-like intracellular cholesterol transporter 1 (NPC1L1)
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)
Recombinant expressionOrganism: Homo sapiens (human)

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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: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 147.640188 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ELYTPKHEAG VCTFYEECGK NPELSGGLTS LSNVSCLSNT PARHVTGEHL ALLQRICPRL YNGPNTTFAC CSTKQLLSLE SSMSITKAL LTRCPACSDN FVSLHCHNTC SPDQSLFINV TRVVERGAGE PPAVVAYEAF YQRSFAEKAY ESCSQVRIPA A ASLAVGSM ...String:
ELYTPKHEAG VCTFYEECGK NPELSGGLTS LSNVSCLSNT PARHVTGEHL ALLQRICPRL YNGPNTTFAC CSTKQLLSLE SSMSITKAL LTRCPACSDN FVSLHCHNTC SPDQSLFINV TRVVERGAGE PPAVVAYEAF YQRSFAEKAY ESCSQVRIPA A ASLAVGSM CGVYGSALCN AQRWLNFQGD TGNGLAPLDI TFHLLEPGQA LPDGIQPLNG KIAPCNESQG DDSAVCSCQD CA ASCPVIP PPEALRPSFY MGRMPGWLAL IIIFTAVFVL LSAVLVRLRV VSNRNKNKAE GPQEAPKLPH KHKLSPHTIL GRF FQNWGT RVASWPLTVL ALSFIVVIAL AAGLTFIELT TDPVELWSAP KSQARKEKSF HDEHFGPFFR TNQIFVTARN RSSY KYDSL LLGSKNFSGI LSLDFLLELL ELQERLRHLQ VWSPEAERNI SLQDICYAPL NPYNTSLSDC CVNSLLQYFQ NNRTL LMLT ANQTLNGQTS LVDWKDHFLY CANAPLTFKD GTSLALSCMA DYGAPVFPFL AVGGYQGTDY SEAEALIITF SLNNYP ADD PRMAQAKLWE EAFLKEMESF QRNTSDKFQV AFSAERSLED EINRTTIQDL PVFAVSYIIV FLYISLALGS YSRCSRV AV ESKATLGLGG VIVVLGAVLA AMGFYSYLGV PSSLVIIQVV PFLVLAVGAD NIFIFVLEYQ RLPRMPGEQR EAHIGRTL G SVAPSMLLCS LSEAICFFLG ALTPMPAVRT FALTSGLAII LDFLLQMTAF VALLSLDSKR QEASRPDVLC CFSTRKLPP PKEKEGLLLR FFRKIYAPFL LHRFIRPVVM LLFLTLFGAN LYLMCNINVG LDQELALPKD SYLIDYFLFL NRYLEVGPPV YFVTTSGFN FSSEAGMNAT CSSAGCKSFS LTQKIQYASE FPDQSYVAIA ASSWVDDFID WLTPSSSCCR LYIRGPHKDE F CPSTDTSF NCLKNCMNRT LGPVRPTAEQ FHKYLPWFLN DPPNIRCPKG GLAAYRTSVN LSSDGQVIAS QFMAYHKPLR NS QDFTEAL RASRLLAANI TADLRKVPGT DPNFEVFPYT ISNVFYQQYL TVLPEGIFTL ALCFVPTFVV CYLLLGLDMC SGI LNLLSI IMILVDTIGL MAVWGISYNA VSLINLVTAV GMSVEFVSHI TRSFAVSTKP TRLERAKDAT VFMGSAVFAG VAMT NFPGI LILGFAQAQL IQIFFFRLNL LITLLGLLHG LVFLPVVLSY LGPDVNQALV QEEKLASEAA VAPEPSCPQY PSPAD ADAN VNYGFAPELA HGANAARSSL PKSDQKFENL YFQGDYKDDD DKHHHHHHHH HH

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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: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 1 / 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

Concentration5 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 46.76 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
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

CTF correctionSoftware - Name: Gctf (ver. 1.06)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3) / Number images used: 144908
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)

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