9OMV

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

This is a non-PDB format compatible entry.

Replaces:  9DZU

Summary for 9OMV

• Entry DOI: 10.2210/pdb9omv/pdb
• EMDB information: 70618
• Descriptor: 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)
• Functional Keywords: cryptococcus neoformans, lipid flippase, p4-atpase, cdc50 protein, butyrolactol a, translocase-inhibitor complex, translocase/inhibitor
• Biological source: Cryptococcus neoformans var. grubii H99; More
• Total number of polymer chains: 2
• Total formula weight: 225232.52

Authors

Duan, H.D.,Li, H. (deposition date: 2025-05-14, release date: 2025-10-22, Last modification date: 2026-02-04)

Primary citation

Chen, X.,Duan, H.D.,Hoy, M.J.,Koteva, K.,Spitzer, M.,Guitor, A.K.,Puumala, E.,Fiebig, A.A.,Hu, G.,Yiu, B.,Chou, S.,Bian, Z.,Choi, Y.,Guo, A.B.Y.,Wang, W.,Sun, S.,Robbins, N.,Averette, A.F.,Cook, M.A.,Truant, R.,MacNeil, L.T.,Brown, E.D.,Kronstad, J.W.,Coombes, B.K.,Cowen, L.E.,Heitman, J.,Li, H.,Wright, G.D.
Butyrolactol A enhances caspofungin efficacy via flippase inhibition in drug-resistant fungi.
Cell, 189:620-, 2026

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

PubMed: 41478284
DOI: 10.1016/j.cell.2025.11.036

Experimental method

ELECTRON MICROSCOPY (2.95 Å)