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TitleFunctional implications of the conformational landscape of a multidrug transporter revealed by Zebrafish Abcb4 structures.
Journal, issue, pagesNat Commun, Year 2026
Publish dateMay 30, 2026
AuthorsJingyu Zhan / Chao-Ming Hsieh / Lothar Esser / Zabrina C Lang / Abraham J Morton / Robert Robey / Fei Zhou / Suresh V Ambudkar / Rick K Huang / Michael M Gottesman / Di Xia /
PubMed AbstractThe hallmark of multidrug resistance conferred by the human ABC transporter ABCB1 (hP-gp) is the recognition and efflux of a diverse range of drugs, though the precise mechanism of polyspecificity ...The hallmark of multidrug resistance conferred by the human ABC transporter ABCB1 (hP-gp) is the recognition and efflux of a diverse range of drugs, though the precise mechanism of polyspecificity remains unresolved. In aquatic animals such as zebrafish, Abcb4, a functional homolog of hP-gp, plays a vital role in surviving environmental toxicants. Here, we show that DrAbcb4 exhibits comparable basal and drug-stimulated ATPase activity to hP-gp. Using cryo-EM, we capture five inward-facing DrAbcb4 conformations with varying separations between its two lobes, illustrating its open-and-close motion. The range of separation exceeds that seen in published P-gp structures that appear to be conformationally restricted. This global open-and-close motion is coupled with individual helix movement, resulting in a highly fluid substrate-binding pocket. These dynamic changes, likely underlying the polyspecificity of substrate recognition, predict unconventional protein-ligand interactions that are supported by structures of DrAbcb4 bound to the P-gp inhibitors tariquidar and elacridar, and the substrate vincristine.
External linksNat Commun / PubMed:42218127
MethodsEM (single particle)
Resolution3.0 - 4.09 Å
Structure data

EMDB-70380, PDB-9ody:
Zebrafish Abcb4 in IF-narrow conformation (IF-Narrow)
Method: EM (single particle) / Resolution: 3.29 Å

EMDB-70381, PDB-9odz:
Zebrafish Abcb4 in IF-Wide conformation (IF-Wide)
Method: EM (single particle) / Resolution: 3.59 Å

EMDB-70382, PDB-9oe0:
Zebrafish Abcb4 in IF-Medium conformation (IF-Medium)
Method: EM (single particle) / Resolution: 3.39 Å

EMDB-70383, PDB-9oe1:
Zebrafish Abcb4 in IF-narrow conformation in the presence of Tariquidar (TQR-IF-Narrow)
Method: EM (single particle) / Resolution: 3.02 Å

EMDB-70384, PDB-9oe2:
Zebrafish Abcb4 in IF-medium conformation in the presence of Tariquidar (TQR-IF-Medium)
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-70386, PDB-9oe4:
Zebrafish Abcb4 in IF-Narrow conformation in the presence of Elacridar (ELA-IF-Narrow)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-70387, PDB-9oe5:
Zebrafish Abcb4 in IF-Medium conformation in the presence of Elacridar (ELA-IF-Medium)
Method: EM (single particle) / Resolution: 3.16 Å

EMDB-70388, PDB-9oe6:
Zebrafish Abcb4 in IF-Wide conformation in the presence of Elacridar (ELA-IF-Wide)
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-70389, PDB-9oe7:
Zebrafish Abcb4 in IF-narrow conformation in the presence of Vincristine (VCR-IF-Narrow)
Method: EM (single particle) / Resolution: 3.95 Å

EMDB-70390, PDB-9oe8:
Zebrafish Abcb4 in IF-medium conformation in the presence of Vincristine (VCR-IF-Medium)
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-70391, PDB-9oe9:
Zebrafish Abcb4 in IF-Wide conformation in the presence of Vincristine (VCR-IF-Wide)
Method: EM (single particle) / Resolution: 4.09 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-HOH:
WATER

ChemComp-R1H:
tariquidar

ChemComp-CLR:
CHOLESTEROL

ChemComp-R0Z:
elacridar

ChemComp-CHD:
CHOLIC ACID

ChemComp-R1Q:
vincristine

Source
  • danio rerio (zebrafish)
KeywordsTRANSPORT PROTEIN / Multidrug resistance / Zebrafish Abcb4 / P-gp / Tariquidar / Elacridar / Vincristine

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