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TitleStructures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment.
Journal, issue, pagesCommun Biol, Vol. 5, Issue 1, Page 7, Year 2022
Publish dateJan 10, 2022
AuthorsLe Thi My Le / James Robert Thompson / Phuoc Xuan Dang / Janarjan Bhandari / Amer Alam /
PubMed AbstractThe 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.
External linksCommun Biol / PubMed:35013584 / PubMed Central
MethodsEM (single particle)
Resolution3.5 - 4.4 Å
Structure data

24656

7rr9

EMDB-24656, PDB-7rr9:
Cryo-EM Structure of Nanodisc reconstituted ABCD1 in nucleotide bound outward open conformation
Method: EM (single particle) / Resolution: 3.5 Å

24657

7rra

EMDB-24657, PDB-7rra:
Cryo-EM Structure of Nanodisc reconstituted ABCD1 in inward open conformation
Method: EM (single particle) / Resolution: 4.4 Å

Chemicals


ChemComp, No image

ChemComp-UNL:
Unknown ligand

ChemComp-CLR:
CHOLESTEROL

ChemComp-MG:
Unknown entry

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / VLCFA ABC transporter ABCD1

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