Structural highlights
Disease
[MDR1_HUMAN] Ulcerative colitis. Disease susceptibility is associated with variations affecting the gene represented in this entry.
Function
[MDR1_HUMAN] Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Publication Abstract from PubMed
The multidrug transporter P-glycoprotein is an 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 electron cryo-microscopy at 3.4-A 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 re-orientated 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.
Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation.,Kim Y, Chen J Science. 2018 Jan 25. pii: science.aar7389. doi: 10.1126/science.aar7389. PMID:29371429[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kim Y, Chen J. Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science. 2018 Jan 25. pii: science.aar7389. doi: 10.1126/science.aar7389. PMID:29371429 doi:http://dx.doi.org/10.1126/science.aar7389
