+Open data
-Basic information
Entry | Database: PDB / ID: 7n4v | ||||||
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Title | Structure of cholesterol-bound human NPC1L1 | ||||||
Components | Isoform 2 of NPC1-like intracellular cholesterol transporter 1 | ||||||
Keywords | MEMBRANE PROTEIN / transporter | ||||||
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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.58 Å | ||||||
Authors | Li, X. / Long, T. | ||||||
Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7n4v.cif.gz | 388.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7n4v.ent.gz | 319.9 KB | Display | PDB format |
PDBx/mmJSON format | 7n4v.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7n4v_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 7n4v_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | 7n4v_validation.xml.gz | 59.6 KB | Display | |
Data in CIF | 7n4v_validation.cif.gz | 85.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/n4/7n4v ftp://data.pdbj.org/pub/pdb/validation_reports/n4/7n4v | HTTPS FTP |
-Related structure data
Related structure data | 24179MC 7n4uC 7n4xC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 145904.031 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: NPC1L1 / Production host: Homo sapiens (human) / References: UniProt: Q9UHC9 #2: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #3: Sugar | ChemComp-NAG / #4: Chemical | ChemComp-CLR / #5: Chemical | Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Human NPC1L1 supplemented with cholesterol / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: DARK FIELD |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 251678 / Symmetry type: POINT |