9IUK の概要
| エントリーDOI | 10.2210/pdb9iuk/pdb |
| EMDBエントリー | 60908 |
| 分子名称 | Pleiotropic ABC efflux transporter of multiple drugs CDR1, Pip2(20:4/18:0) (2 entities in total) |
| 機能のキーワード | abc transporters, pleiotropic drug resistance, membrane protein, transport protein |
| 由来する生物種 | Candida albicans SC5314 |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 171206.74 |
| 構造登録者 | |
| 主引用文献 | Peng, Y.,Lu, Y.,Sun, H.,Ma, J.,Li, X.,Han, X.,Fang, Z.,Tan, J.,Qiu, Y.,Qu, T.,Yin, M.,Yan, Z. Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms. Nat Commun, 15:7722-7722, 2024 Cited by PubMed Abstract: 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), fluconazole-bound state (Cdr1), and milbemycin oxime-inhibited state (Cdr1). 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. PubMed: 39242571DOI: 10.1038/s41467-024-52107-w 主引用文献が同じPDBエントリー |
| 実験手法 | ELECTRON MICROSCOPY (3.38 Å) |
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