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TitleVisualizing the Functional Dynamics of P-Glycoprotein and Its Modulation by Elacridar via High-Speed Atomic Force Microscopy.
Journal, issue, pagesInt J Mol Sci, Vol. 27, Issue 1, Year 2025
Publish dateDec 29, 2025
AuthorsYui Kanaoka / Norie Hamaguchi-Suzuki / Yuto Nonaka / Soichi Yamashita / Osamu Miyashita / Atsuyuki Ito / Satoshi Ogasawara / Florence Tama / Takeshi Murata / Takayuki Uchihashi /
PubMed AbstractP-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well- ...P-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well-established that P-gp functions through conformational changes, yet its large-scale structural dynamics at work have been unexplored. Here, we directly visualized single P-gp molecules reconstituted in nanodiscs using high-speed atomic force microscopy (HS-AFM). The HS-AFM movies revealed that P-gp is intrinsically dynamic in its apo state, with its nucleotide-binding domains (NBDs) undergoing large, spontaneous opening and closing motions. However, addition of ATP stabilized a conformation characterized by NBD proximity with a strong tendency toward closure. We then leveraged this dynamic viewpoint to elucidate the relationship between Elacridar's function and the resulting structural dynamics of P-gp. Elacridar is designed to overcome multidrug resistance (MDR) in cancer and acts as a potent dual inhibitor of both P-gp and the Breast Cancer Resistance Protein (BCRP), effectively blocking the drug efflux function of these transporters. This inhibitor has suggested concentration-dependent function: it is effluxed as a substrate at low concentrations and acts as an inhibitor at high concentrations. Our direct observations revealed that low concentrations induced active dynamics in P-gp, whereas high concentrations severely restricted its motion, leading to a rigid, non-productive state. Our study provides critical insights into how observing molecular motion itself can unravel complex biological mechanisms.
External linksInt J Mol Sci / PubMed:41516232 / PubMed Central
MethodsEM (single particle)
Resolution7.17 - 7.91 Å
Structure data

EMDB-66042: Open State of Apo-P-Glycoprotein
Method: EM (single particle) / Resolution: 7.91 Å

EMDB-66043: Closed State of Apo-P-Glycoprotein.
Method: EM (single particle) / Resolution: 7.17 Å

Source
  • Homo sapiens (human)

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