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| Title | Functional implications of the conformational landscape of a multidrug transporter revealed by Zebrafish Abcb4 structures. |
|---|---|
| Journal, issue, pages | Nat Commun, Year 2026 |
| Publish date | May 30, 2026 |
Authors | Jingyu 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 Abstract | 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 ...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 links | Nat Commun / PubMed:42218127 |
| Methods | EM (single particle) |
| Resolution | 3.0 - 4.09 Å |
| Structure data | EMDB-70380, PDB-9ody: EMDB-70381, PDB-9odz: EMDB-70382, PDB-9oe0: EMDB-70383, PDB-9oe1: EMDB-70384, PDB-9oe2: EMDB-70386, PDB-9oe4: EMDB-70387, PDB-9oe5: EMDB-70388, PDB-9oe6: EMDB-70389, PDB-9oe7: EMDB-70390, PDB-9oe8: EMDB-70391, PDB-9oe9: |
| Chemicals | ![]() ChemComp-MG: ![]() ChemComp-AGS: ![]() ChemComp-HOH: ![]() ChemComp-R1H: ![]() ChemComp-CLR: ![]() ChemComp-R0Z: ![]() ChemComp-CHD: ![]() ChemComp-R1Q: |
| Source |
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Keywords | TRANSPORT PROTEIN / Multidrug resistance / Zebrafish Abcb4 / P-gp / Tariquidar / Elacridar / Vincristine |
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