9IUM

The structure of Candida albicans Cdr1 in milbemycin oxime-inhibited state

This is a non-PDB format compatible entry.

Summary for 9IUM

• Entry DOI: 10.2210/pdb9ium/pdb
• EMDB information: 60910
• Descriptor: Pleiotropic ABC efflux transporter of multiple drugs CDR1, Pip2(20:4/18:0), milbemycin oxime (3 entities in total)
• Functional Keywords: abc transporters, pleiotropic drug resistance, membrane protein, transport protein
• Biological source: Candida albicans SC5314
• Total number of polymer chains: 1
• Total formula weight: 171762.45

Authors

Peng, Y.,Sun, H.,Yan, Z.F. (deposition date: 2024-07-22, release date: 2024-09-18, Last modification date: 2024-11-06)

Primary citation

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

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: 39242571
DOI: 10.1038/s41467-024-52107-w

Experimental method

ELECTRON MICROSCOPY (3.08 Å)