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Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms

Author

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  • Ying Peng

    (Hunan University)

  • Yan Lu

    (Hunan University)

  • Hui Sun

    (Hunan University)

  • Jinying Ma

    (Tsinghua University)

  • Xiaomei Li

    (Shanxi Academy of Advanced Research and Innovation)

  • Xiaodan Han

    (Hunan University)

  • Zhixiong Fang

    (Hunan University)

  • Junming Tan

    (Hunan University)

  • Yingchen Qiu

    (Hunan University)

  • Tingting Qu

    (Hunan University)

  • Meng Yin

    (Hunan University)

  • Zhaofeng Yan

    (Hunan University)

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 (Cdr1Apo), fluconazole-bound state (Cdr1Flu), and milbemycin oxime-inhibited state (Cdr1Mil). 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.

Suggested Citation

  • Ying Peng & Yan Lu & Hui Sun & Jinying Ma & Xiaomei Li & Xiaodan Han & Zhixiong Fang & Junming Tan & Yingchen Qiu & Tingting Qu & Meng Yin & Zhaofeng Yan, 2024. "Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52107-w
    DOI: 10.1038/s41467-024-52107-w
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