View source for 9dzv


==Cryo-EM structure of the C. neoformans lipid flippase Apt1-Cdc50 in the E1 state==
<StructureSection load='9dzv' size='340' side='right'caption='[[9dzv]], [[Resolution|resolution]] 3.27&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9dzv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryptococcus_neoformans_var._grubii_H99 Cryptococcus neoformans var. grubii H99]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9DZV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DZV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.27&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9dzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9dzv OCA], [https://pdbe.org/9dzv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9dzv RCSB], [https://www.ebi.ac.uk/pdbsum/9dzv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9dzv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/J9VW44_CRYNH J9VW44_CRYNH] 
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== 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 Apt1âbutyrolactol 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<ref>PMID:39829750</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9dzv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Cryptococcus neoformans var. grubii H99]]
[[Category: Large Structures]]
[[Category: Duan HD]]
[[Category: Li H]]