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Structure paper

TitleCryo-EM structures of Cdr1 reveal snapshots of substrate transport and diverse inhibitor recognition.
Journal, issue, pagesSci Adv, Vol. 12, Issue 35, Page eaef7706, Year 2026
Publish dateAug 28, 2026
AuthorsZhen Wang / Shuting Yang / Binyu Zhang / Hengyi Jiang / Yinxia Li / Rongchao Gao / Yulong Wang / Fengying Fan / Lili Dong / Jiaxuan Qiu / Xiurui Li / Yue Zhou / Alastair I H Murchie / Xuekui Yu /
PubMed AbstractIn -a World Health Organization fungal priority pathogen-overexpression of the adenosine triphosphate (ATP)-binding cassette transporter Cdr1 drives multidrug resistance. We present seven cryo- ...In -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.
External linksSci Adv / PubMed:42664345 / PubMed Central
MethodsEM (single particle)
Resolution2.41 - 2.95 Å
Structure data

EMDB-65307, PDB-9vsu:
Structure of Cdr1 with Tacrolimus
Method: EM (single particle) / Resolution: 2.82 Å

EMDB-65308, PDB-9vsv:
Structure of Cdr1 with curcumin
Method: EM (single particle) / Resolution: 2.82 Å

EMDB-65309, PDB-9vsw:
Structure of Cdr1 with beauvericin
Method: EM (single particle) / Resolution: 2.95 Å

EMDB-65311, PDB-9vsz:
Structure of Cdr1 with Fluconazole at the near site
Method: EM (single particle) / Resolution: 2.93 Å

EMDB-65312, PDB-9vt1:
Structure of Cdr1 with ATP/ADP
Method: EM (single particle) / Resolution: 2.46 Å

EMDB-65313, PDB-9vt2:
Structure of Cdr1 with Fluconazole at the middle site
Method: EM (single particle) / Resolution: 2.79 Å

EMDB-65335, PDB-9vtm:
Structure of Cdr1 with AMPPNP
Method: EM (single particle) / Resolution: 2.92 Å

EMDB-65336, PDB-9vtn:
Structure of Cdr1 with AMPPNP and the far site Fluconazole
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-65337, PDB-9vto:
Structure of Cdr1 with AMPPNP/AMPPNP
Method: EM (single particle) / Resolution: 2.41 Å

EMDB-68246, PDB-22fr:
Structure of apo Cdr1
Method: EM (single particle) / Resolution: 2.74 Å

Chemicals

ChemComp-FK5:
8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN / medication*YM

ChemComp-CC9:
curcumin

ChemComp-TPF:
2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL / medication, antifungal*YM

ChemComp-MG:
Unknown entry

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-HOH:
WATER

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

Source
  • candida albicans sc5314 (yeast)
  • Candida albicans (strain SC5314 / ATCC MYA-2876) (yeast)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / Candida albicans / Multidrug resistance / Substrate efflux cycle / TRANSPORT PROTEIN / Inhibitor

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