6C0V

Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation

Summary for 6C0V

• Entry DOI: 10.2210/pdb6c0v/pdb
• EMDB information: 7325
• Descriptor: Multidrug resistance protein 1, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION (3 entities in total)
• Functional Keywords: abc transporter; abcb1; p-glycoprotein; cryo-em; multidrug resistance, structural genomics, psi-2, protein structure initiative, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 143723.89

Authors

Kim, Y.J.,Chen, J. (deposition date: 2018-01-02, release date: 2018-01-31, Last modification date: 2024-03-13)

Primary citation

Kim, Y.,Chen, J.
Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation.
Science, 359:915-919, 2018

PubMed 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.

PubMed: 29371429
DOI: 10.1126/science.aar7389

Experimental method

ELECTRON MICROSCOPY (3.4 Å)