Cryo-EM structures of Cdr1 reveal snapshots of substrate transport and diverse inhibitor recognition

-a World Health Organization fungal priority pathogen-overexpression of the adenosine triphosphate (ATP)-binding cassette transporter Cdr1 drives multidrug resistance. We present seven cryo-electron microscopy structures capturing substrate entry and expulsion. An inward-facing transmembrane channel with three on-off substrate binding sites defines a proposed entry pathway for a single substrate molecule. Coordinated ATP binding to both nucleotide-binding domains induces transmembrane domain closure, driving the substrate expulsion; adenosine diphosphate release following ATP hydrolysis resets the transporter to an inward-open conformation, enabling substrate entry for the next translocation cycle. Structures with three structurally diverse inhibitors resolve two distinct binding modes: one occupying all three substrate sites and another specifically binding two extracellular-proximal sites. These findings provide snapshots of the substrate translocation cycle and structural blueprints for antifungal drug design.

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Publication Details

Journal
Science Advances
Published
2026-08-28
DOI
https://doi.org/10.1126/sciadv.aef7706
Primary Topic
Drug Transport and Resistance Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Cryo-EM structures of Cdr1 reveal snapshots of substrate transport and diverse inhibitor recognition

Xuekui Yu, Alastair I.H. Murchie, Rongchao Gao, Yulong Wang et al.
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Cryo-EM structures of Cdr1 reveal snapshots of substrate transport and diverse inhibitor recognition

Xuekui Yu, Alastair I.H. Murchie, Rongchao Gao, Yulong Wang, Hengyi Jiang, Zhen Wang, Lili Dong, Yue Zhou, Jiaxuan Qiu, Shuting Yang, Binyu Zhang, Fengying Fan, Yinxia Li, Xiurui Li
article en

Abstract

-a World Health Organization fungal priority pathogen-overexpression of the adenosine triphosphate (ATP)-binding cassette transporter Cdr1 drives multidrug resistance. We present seven cryo-electron microscopy structures capturing substrate entry and expulsion. An inward-facing transmembrane channel with three on-off substrate binding sites defines a proposed entry pathway for a single substrate molecule. Coordinated ATP binding to both nucleotide-binding domains induces transmembrane domain closure, driving the substrate expulsion; adenosine diphosphate release following ATP hydrolysis resets the transporter to an inward-open conformation, enabling substrate entry for the next translocation cycle. Structures with three structurally diverse inhibitors resolve two distinct binding modes: one occupying all three substrate sites and another specifically binding two extracellular-proximal sites. These findings provide snapshots of the substrate translocation cycle and structural blueprints for antifungal drug design.

Science AdvancesVol. 12(35)
Nanjing University of Chinese Medicine (CN), Shanghai Medical College of Fudan University (CN), Chinese Academy of Sciences (CN), Fudan University (CN), Shanghai Institute of Materia Medica (CN), Pudong Medical Center (CN), University of Chinese Academy of Sciences (CN)
Natural Science Foundation of Shanghai, National Natural Science Foundation of China
Good health and well-being
Openalex Percentile: Top 13%
Drug Transport and Resistance Mechanisms
DOIOpen Access PDFOpenAlex
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