7XEC

Cryo-EM structure of human ABCD1 E630Q in the presence of ATP in inward-facing state 2

Summary for 7XEC

• Entry DOI: 10.2210/pdb7xec/pdb
• EMDB information: 33155
• Descriptor: ATP-binding cassette sub-family D member 1, ADENOSINE-5'-TRIPHOSPHATE (2 entities in total)
• Functional Keywords: membrane protein, complex, ligand, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 166586.93

Authors

Chao, X.,Li-Na, J.,Lin, T. (deposition date: 2022-03-30, release date: 2023-03-29, Last modification date: 2024-06-26)

Primary citation

Xiong, C.,Jia, L.N.,Xiong, W.X.,Wu, X.T.,Xiong, L.L.,Wang, T.H.,Zhou, D.,Hong, Z.,Liu, Z.,Tang, L.
Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP.
Signal Transduct Target Ther, 8:74-74, 2023

PubMed Abstract: Dysfunctions of ATP-binding cassette, subfamily D, member 1 (ABCD1) cause X-linked adrenoleukodystrophy, a rare neurodegenerative disease that affects all human tissues. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long-chain fatty acids for their β-oxidation. Here, the six cryo-electron microscopy structures of ABCD1 in four distinct conformational states were presented. In the transporter dimer, two transmembrane domains form the substrate translocation pathway, and two nucleotide-binding domains form the ATP-binding site that binds and hydrolyzes ATP. The ABCD1 structures provide a starting point for elucidating the substrate recognition and translocation mechanism of ABCD1. Each of the four inward-facing structures of ABCD1 has a vestibule that opens to the cytosol with variable sizes. Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane domains (TMDs) and stimulates the ATPase activity of the nucleotide-binding domains (NBDs). W339 from the transmembrane helix 5 (TM5) is essential for binding substrate and stimulating ATP hydrolysis by substrate. ABCD1 has a unique C-terminal coiled-coil domain that negatively modulates the ATPase activity of the NBDs. Furthermore, the structure of ABCD1 in the outward-facing state indicates that ATP molecules pull the two NBDs together and open the TMDs to the peroxisomal lumen for substrate release. The five structures provide a view of the substrate transport cycle and mechanistic implication for disease-causing mutations.

PubMed: 36810450
DOI: 10.1038/s41392-022-01280-9

Experimental method

ELECTRON MICROSCOPY (3.34 Å)