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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-24179 | |||||||||
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Title | Structure of cholesterol-bound human NPC1L1 | |||||||||
![]() | Structure of cholesterol-bound human NPC1L1 | |||||||||
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Function / homology | ![]() 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 | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.58 Å | |||||||||
![]() | Li X / Long T | |||||||||
![]() | ![]() 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 |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 167.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 10.9 KB 10.9 KB | Display Display | ![]() |
Images | ![]() | 87.9 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7n4vMC ![]() 7n4uC ![]() 7n4xC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Structure of cholesterol-bound human NPC1L1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.833 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : Human NPC1L1 supplemented with cholesterol
Entire | Name: Human NPC1L1 supplemented with cholesterol |
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Components |
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-Supramolecule #1: Human NPC1L1 supplemented with cholesterol
Supramolecule | Name: Human NPC1L1 supplemented with cholesterol / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
-Macromolecule #1: Isoform 2 of NPC1-like intracellular cholesterol transporter 1
Macromolecule | Name: Isoform 2 of NPC1-like intracellular cholesterol transporter 1 type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 145.904031 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 8 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #4: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 6 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-Macromolecule #5: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...
Macromolecule | Name: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate type: ligand / ID: 5 / Number of copies: 2 / Formula: POV |
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Molecular weight | Theoretical: 760.076 Da |
Chemical component information | ![]() ChemComp-POV: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DARK FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 251678 |
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Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |