8JW4

Cryo-EM structure of Plasmodium falciparum multidrug resistance protein 1 in the apo state without H1 helix

8JW4 の概要

• エントリーDOI: 10.2210/pdb8jw4/pdb
• EMDBエントリー: 36674 36679
• 分子名称: Multidrug resistance protein 1 (1 entity in total)
• 機能のキーワード: plasmodium falciparum, multidrug resistance protein 1, abc transporter, apo state, transport protein
• 由来する生物種: Plasmodium falciparum (isolate 3D7)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 162764.81

構造登録者

Li, M.,Si, K. (登録日: 2023-06-28, 公開日: 2023-08-30)

主引用文献

Si, K.,He, X.,Chen, L.,Zhang, A.,Guo, C.,Li, M.
The structure of Plasmodium falciparum multidrug resistance protein 1 reveals an N-terminal regulatory domain.
Proc.Natl.Acad.Sci.USA, 120:e2219905120-e2219905120, 2023

PubMed Abstract: multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is associated with the resistance to antimalarial drugs. To understand the mechanisms of PfMDR1, we determined the cryo-electron microscopy structures of this transporter in different states. The transporter in the apo state shows an inward-facing conformation with a large cavity opening to the cytoplasm. Upon ATP binding and dimerization of the nucleotide-binding domains (NBDs), PfMDR1 displays an outward-facing conformation with a cavity toward the DV lumen. Drug resistance-associated mutations were investigated in both structures for their effects, and Y184F was identified as an allosteric activity-enhancing mutation. The amphiphilic substrate-binding site of PfMDR1 was revealed by the complex structure with the antimalarial drug mefloquine and confirmed by mutagenesis studies. Remarkably, a helical structure was found to hinder NBD dimerization and inhibit PfMDR1 activity. The location of this regulatory domain in the N terminus is different from the well-studied R domain in the internal linker region of other ABC transporter family members. The lack of the phosphorylation site of this domain also suggests a different regulation mechanism.

PubMed: 37527341
DOI: 10.1073/pnas.2219905120

実験手法

ELECTRON MICROSCOPY (3.13 Å)