9dzv | pdb_00009dzv

Cryo-EM structure of the C. neoformans lipid flippase Apt1-Cdc50 in the E1 state

spinqualitylabelsall models 9dzv, resolution 3.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9dzv is a 2 chain structure with sequence from Cryptococcus neoformans var. grubii H99. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.27Å Ligands: BMA, MAN, MG, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function J9VW44_CRYNH Publication Abstract from PubMed 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 Candida auris , 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 Cryptococcus neoformans H99, identifying butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including C. auris . 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. Butyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi.,Chen X, Duan HD, Hoy MJ, Koteva K, Spitzer M, Guitor AK, Puumala E, Hu G, Yiu B, Chou S, Bian Z, Guo ABY, Sun S, Robbins N, Cook MA, Truant R, MacNeil LT, Brown ED, Kronstad JW, Cowen LE, Heitman J, Li H, Wright GD bioRxiv [Preprint]. 2025 Jan 6:2025.01.06.630955. doi: 10.1101/2025.01.06.630955. PMID:39829750 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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