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Yorodumi- PDB-7rr9: Cryo-EM Structure of Nanodisc reconstituted ABCD1 in nucleotide b... -
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-Basic information
Entry | Database: PDB / ID: 7rr9 | |||||||||
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Title | Cryo-EM Structure of Nanodisc reconstituted ABCD1 in nucleotide bound outward open conformation | |||||||||
Components | ATP-binding cassette sub-family D member 1 | |||||||||
Keywords | TRANSPORT PROTEIN / VLCFA ABC transporter ABCD1 | |||||||||
Function / homology | Function and homology information ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / very long-chain fatty acyl-CoA hydrolase activity / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / alpha-linolenic acid metabolic process / long-chain fatty acid catabolic process / alpha-linolenic acid (ALA) metabolism ...ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / very long-chain fatty acyl-CoA hydrolase activity / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / alpha-linolenic acid metabolic process / long-chain fatty acid catabolic process / alpha-linolenic acid (ALA) metabolism / long-chain fatty acid import into peroxisome / very long-chain fatty acid catabolic process / Beta-oxidation of very long chain fatty acids / regulation of fatty acid beta-oxidation / very long-chain fatty acid metabolic process / sterol homeostasis / Class I peroxisomal membrane protein import / peroxisome organization / regulation of mitochondrial depolarization / ABC transporters in lipid homeostasis / fatty acyl-CoA hydrolase activity / myelin maintenance / regulation of cellular response to oxidative stress / Hydrolases; Acting on ester bonds; Thioester hydrolases / linoleic acid metabolic process / positive regulation of fatty acid beta-oxidation / regulation of oxidative phosphorylation / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / fatty acid elongation / peroxisomal membrane / long-chain fatty acid transmembrane transporter activity / fatty acid beta-oxidation / ATPase-coupled transmembrane transporter activity / negative regulation of cytokine production involved in inflammatory response / fatty acid homeostasis / negative regulation of reactive oxygen species biosynthetic process / neuron projection maintenance / mitochondrial membrane / ADP binding / peroxisome / protein heterodimerization activity / lysosomal membrane / endoplasmic reticulum membrane / perinuclear region of cytoplasm / enzyme binding / protein homodimerization activity / ATP hydrolysis activity / ATP binding / identical protein binding / membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å | |||||||||
Authors | Alam, A. / Le, L.T.M. / Thompson, J.R. | |||||||||
Funding support | United States, 2items
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Citation | Journal: Commun Biol / Year: 2022 Title: Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment. Authors: Le Thi My Le / James Robert Thompson / Phuoc Xuan Dang / Janarjan Bhandari / Amer Alam / Abstract: The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, ...The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive demyelination, and neurological impairments including X-linked adrenoleukodystrophy (X-ALD). We present cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution, revealing details of its transmembrane cavity and ATP dependent conformational spectrum. We identify features distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Our data suggest a transport mechanism where the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane domain while the acyl chains extend out into the surrounding membrane bilayer. The structures help rationalize disease causing mutations and may aid ABCD1 targeted structure-based drug design. | |||||||||
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 | 7rr9.cif.gz | 213.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7rr9.ent.gz | 168.7 KB | Display | PDB format |
PDBx/mmJSON format | 7rr9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7rr9_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 7rr9_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 7rr9_validation.xml.gz | 35.4 KB | Display | |
Data in CIF | 7rr9_validation.cif.gz | 53 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/rr/7rr9 ftp://data.pdbj.org/pub/pdb/validation_reports/rr/7rr9 | HTTPS FTP |
-Related structure data
Related structure data | 24656MC 7rraC 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: 83040.867 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ABCD1, ALD / Production host: Homo sapiens (human) / References: UniProt: P33897, EC: 7.6.2.4 #2: Chemical | Mass: 734.039 Da / Num. of mol.: 2 / Source method: obtained synthetically / Feature type: SUBJECT OF INVESTIGATION #3: Chemical | #4: Chemical | #5: Chemical | Has ligand of interest | Y | |
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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 ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs / Type: COMPLEX Details: Human ABCD1 recombinantly expressed in HEK293 TREX cell line and reconstituted in MSP1D1 nanodiscs comprising 4:1 mixture of Porcine Brain Polar Lipids:Cholesterol. The reported molecular ...Details: Human ABCD1 recombinantly expressed in HEK293 TREX cell line and reconstituted in MSP1D1 nanodiscs comprising 4:1 mixture of Porcine Brain Polar Lipids:Cholesterol. The reported molecular weight of 0.0829 MDa is for the monomer. The assembly is a homodimer. The dimer was confirmed using SEC. Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 0.0829 MDa / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 Details: 25mM HEPES pH 7.5, 150mM NaCl, 5mM ATP gammaS, 10mM Magnesium Chloride |
Specimen | Conc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277 K |
-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: BRIGHT FIELD / Nominal defocus max: 2600 nm / Nominal defocus min: 800 nm |
Image recording | Average exposure time: 60 sec. / Electron dose: 60 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.20rc3_4406: / Classification: refinement | ||||||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 37237 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: AB INITIO MODEL / Space: REAL | ||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6JBJ Accession code: 6JBJ / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||||||||||||||
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