9DZU
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.
Summary for 9DZU
| Entry DOI | 10.2210/pdb9dzu/pdb |
| EMDB information | 47338 |
| 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: 2024-10-17, release date: 2025-02-05, Last modification date: 2025-05-21) |
| Primary citation | 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 Cited by 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: 39829750DOI: 10.1101/2025.01.06.630955 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.72 Å) |
Structure validation
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