9BS1
Cryo-EM structure of the S. cerevisiae lipid flippase Neo1 bound with PI4P in the E2P state
This is a non-PDB format compatible entry.
Summary for 9BS1
| Entry DOI | 10.2210/pdb9bs1/pdb |
| EMDB information | 44850 |
| Descriptor | Phospholipid-transporting ATPase NEO1, BERYLLIUM TRIFLUORIDE ION, (2R)-3-{[(S)-hydroxy{[(1R,2R,3R,4R,5S,6R)-2,3,5,6-tetrahydroxy-4-(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl di[(9Z)-octadec-9-enoate] (3 entities in total) |
| Functional Keywords | lipid flippase, p4-atpase, pi4p, phosphoinositide, neomycin resistance, lipid transport |
| Biological source | Saccharomyces cerevisiae (brewer's yeast) |
| Total number of polymer chains | 1 |
| Total formula weight | 132369.56 |
| Authors | Duan, H.D.,Li, H. (deposition date: 2024-05-12, release date: 2025-04-02, Last modification date: 2025-07-30) |
| Primary citation | Jain, B.K.,Duan, H.D.,Valentine, C.,Samiha, A.,Li, H.,Graham, T.R. P4-ATPases control phosphoinositide membrane asymmetry and neomycin resistance. Nat.Cell Biol., 27:1114-1124, 2025 Cited by PubMed Abstract: The aminoglycoside antibiotic neomycin has robust antibacterial properties, yet its clinical utility is curtailed by its nephrotoxicity and ototoxicity. The mechanism by which the polycationic neomycin enters specific eukaryotic cell types remains poorly understood. In budding yeast, NEO1 is required for neomycin resistance and encodes a phospholipid flippase that establishes membrane asymmetry. Here we show that mutations altering Neo1 substrate recognition cause neomycin hypersensitivity by exposing phosphatidylinositol-4-phosphate (PI4P) in the plasma membrane extracellular leaflet. Cryogenic electron microscopy reveals PI4P binding to Neo1 within the substrate translocation pathway. PI4P enters the lumen of the endoplasmic reticulum and is flipped by Neo1 at the Golgi to prevent PI4P secretion to the cell surface. Deficiency of the orthologous ATP9A in human cells also causes exposure of PI4P and neomycin sensitivity. These findings unveil conserved mechanisms of aminoglycoside sensitivity and phosphoinositide homoeostasis, with important implications for signalling by extracellular phosphoinositides. PubMed: 40646185DOI: 10.1038/s41556-025-01692-z PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.71 Å) |
Structure validation
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