Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation.
SCIE
SCOPUS
- Title
- Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation.
- Authors
- KIM, YOUNGJIN; Chen, Jue
- Date Issued
- 2018-02
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE
- Abstract
- The multidrug transporter permeability (P)-glycoprotein is an adenosine triphosphate (ATP)-binding cassette exporter responsible for clinical resistance to chemotherapy. P-glycoprotein extrudes toxic molecules and drugs from cells through ATP-powered conformational changes. Despite decades of effort, only the structures of the inward-facing conformation of P-glycoprotein are available. Here we present the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo-electron microscopy at 3.4-angstrom resolution. The two nucleotide-binding domains form a closed dimer occluding two ATP molecules. The drug-binding cavity observed in the inward-facing structures is reorientated toward the extracellular space and compressed to preclude substrate binding. This observation indicates that ATP binding, not hydrolysis, promotes substrate release. The structure evokes a model in which the dynamic nature of P-glycoprotein enables translocation of a large variety of substrates.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/96059
- DOI
- 10.1126/science.aar7389
- ISSN
- 0036-8075
- Article Type
- Article
- Citation
- SCIENCE, vol. 359, no. 6378, page. 915 - 919, 2018-02
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