9DZU

Cryo-EM structure of the C. neoformans lipid flippase Apt1-Cdc50 bound with butyrolactol A in the E2P state

これはPDB形式変換不可エントリーです。

9DZU の概要

• エントリーDOI: 10.2210/pdb9dzu/pdb
• EMDBエントリー: 47338
• 分子名称: Transcription regulator, Phospholipid-transporting ATPase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: cryptococcus neoformans, lipid flippase, p4-atpase, cdc50 protein, butyrolactol a, translocase-inhibitor complex, translocase/inhibitor
• 由来する生物種: Cryptococcus neoformans var. grubii H99; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 225232.52

構造登録者

Duan, H.D.,Li, H. (登録日: 2024-10-17, 公開日: 2025-02-05, 最終更新日: 2025-05-21)

主引用文献

Chen, X.,Duan, H.D.,Hoy, M.J.,Koteva, K.,Spitzer, M.,Guitor, A.K.,Puumala, E.,Hu, G.,Yiu, B.,Chou, S.,Bian, Z.,Guo, A.B.Y.,Sun, S.,Robbins, N.,Cook, M.A.,Truant, R.,MacNeil, L.T.,Brown, E.D.,Kronstad, J.W.,Cowen, L.E.,Heitman, J.,Li, H.,Wright, G.D.
Butyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi.
Biorxiv, 2025

PubMed Abstract: Fungal infections cause millions of deaths annually and are challenging to treat due to limited antifungal options and increasing drug resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while , a notorious global threat, is also increasingly resistant. We performed a natural product extract screen for rescue of the activity of the echinocandin caspofungin against H99, identifying butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including . Mode of action studies revealed that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryoelectron-microscopy analysis of the Apt1●butyrolactol A complex revealed that the flippase is locked in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.

PubMed: 39829750
DOI: 10.1101/2025.01.06.630955

実験手法

ELECTRON MICROSCOPY (2.72 Å)