View source for 9iuk


==The structure of Candida albicans Cdr1 in apo state==
<StructureSection load='9iuk' size='340' side='right'caption='[[9iuk]], [[Resolution|resolution]] 3.38&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9iuk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Candida_albicans_SC5314 Candida albicans SC5314]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9IUK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9IUK 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]] 3.38&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L26:[(2~{R})-2-octadecanoyloxy-3-[oxidanyl-[(1~{S},2~{R},3~{S},4~{S},5~{S},6~{R})-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl]+(5~{E},8~{E},11~{E},14~{E})-icosa-5,8,11,14-tetraenoate'>A1L26</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=9iuk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9iuk OCA], [https://pdbe.org/9iuk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9iuk RCSB], [https://www.ebi.ac.uk/pdbsum/9iuk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9iuk ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CDR1_CANAL CDR1_CANAL] Pleiotropic ABC efflux transporter that confers resistance to numerous chemicals including anisomycin, cycloheximide, fluconazole, miconazole, ketoconazole, itriconazole, nystatin, terbinafine, amorolfine, brefeldin A, amphotericin B, fluphenazine, as well as estrogen. Plays a role in farnesol-induced apoptotic process through glutathione efflux activity. Mediates in-to-out translocation of membrane phospholipids including aminophospholipids and thus regulates asymmetric distribution of phosphatidylethanolamine. Exhibits nucleoside triphosphatase activity.<ref>PMID:10029989</ref> <ref>PMID:10227177</ref> <ref>PMID:10428921</ref> <ref>PMID:11709310</ref> <ref>PMID:11870854</ref> <ref>PMID:12709320</ref> <ref>PMID:14665469</ref> <ref>PMID:15152937</ref> <ref>PMID:15190023</ref> <ref>PMID:15486081</ref> <ref>PMID:15937063</ref> <ref>PMID:16291868</ref> <ref>PMID:16475832</ref> <ref>PMID:16622073</ref> <ref>PMID:16782311</ref> <ref>PMID:17202662</ref> <ref>PMID:18056285</ref> <ref>PMID:18268086</ref> <ref>PMID:18710914</ref> <ref>PMID:19223631</ref> <ref>PMID:19393219</ref> <ref>PMID:20002912</ref> <ref>PMID:20348384</ref> <ref>PMID:20876623</ref> <ref>PMID:22166216</ref> <ref>PMID:22205973</ref> <ref>PMID:23824183</ref> <ref>PMID:23979757</ref> <ref>PMID:8891134</ref> <ref>PMID:9124851</ref> <ref>PMID:9453158</ref> <ref>PMID:9605504</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
In Candida albicans, Cdr1 pumps azole drugs out of the cells to reduce intracellular accumulation at detrimental concentrations, leading to azole-drug resistance. Milbemycin oxime, a veterinary anti-parasitic drug, strongly and specifically inhibits Cdr1. However, how Cdr1 recognizes and exports azole drugs, and how milbemycin oxime inhibits Cdr1 remain unclear. Here, we report three cryo-EM structures of Cdr1 in distinct states: the apo state (Cdr1(Apo)), fluconazole-bound state (Cdr1(Flu)), and milbemycin oxime-inhibited state (Cdr1(Mil)). Both the fluconazole substrate and the milbemycin oxime inhibitor are primarily recognized within the central cavity of Cdr1 through hydrophobic interactions. The fluconazole is suggested to be exported from the binding site into the environment through a lateral pathway driven by TM2, TM5, TM8 and TM11. Our findings uncover the inhibitory mechanism of milbemycin oxime, which inhibits Cdr1 through competition, hindering export, and obstructing substrate entry. These discoveries advance our understanding of Cdr1-mediated azole resistance in C. albicans and provide the foundation for the development of innovative antifungal drugs targeting Cdr1 to combat azole-drug resistance.

Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms.,Peng Y, Lu Y, Sun H, Ma J, Li X, Han X, Fang Z, Tan J, Qiu Y, Qu T, Yin M, Yan Z Nat Commun. 2024 Sep 6;15(1):7722. doi: 10.1038/s41467-024-52107-w. PMID:39242571<ref>PMID:39242571</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9iuk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Candida albicans SC5314]]
[[Category: Large Structures]]
[[Category: Peng Y]]
[[Category: Sun H]]
[[Category: Yan ZF]]