8Z0F

Cryo-EM structure of ATP-bound human very long-chain fatty acid ABC transporter ABCD3

Summary for 8Z0F

• Entry DOI: 10.2210/pdb8z0f/pdb
• EMDB information: 39703
• Descriptor: ATP-binding cassette sub-family D member 3, ADENOSINE-5'-TRIPHOSPHATE (2 entities in total)
• Functional Keywords: very long-chain fatty, peroxisome, abc transporter, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 154370.74

Authors

Li, Y.,Chen, Y.X.,Zhou, C.Z.,Hou, W.T. (deposition date: 2024-04-09, release date: 2024-09-18, Last modification date: 2025-04-23)

Primary citation

Li, Y.,Chen, Z.P.,Xu, D.,Wang, L.,Cheng, M.T.,Zhou, C.Z.,Chen, Y.,Hou, W.T.
Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation.
Cell Discov, 10:92-92, 2024

PubMed Abstract: Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the β-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases.

PubMed: 39223112
DOI: 10.1038/s41421-024-00722-8

Experimental method

ELECTRON MICROSCOPY (3.27 Å)