Journal
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
Volume 71, Issue -, Pages 732-741Publisher
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S1399004715000978
Keywords
P-glycoprotein
Funding
- National Institutes of Health (NIH) [R01 GM94367, R01 ES021985, R01 GM098538, RGM102928]
- NHMRC CJ Martin Postdoctoral Research Fellowship
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P-glycoprotein (P-gp) is a transporter of great clinical and pharmacological significance. Several structural studies of P-gp and its homologs have provided insights into its transport cycle, but questions remain regarding how P-gp recognizes diverse substrates and how substrate binding is coupled to ATP hydrolysis. Here, four new P-gp co-crystal structures with a series of rationally designed ligands are presented. It is observed that the binding of certain ligands, including an ATP-hydrolysis stimulator, produces a large conformational change in the fourth transmembrane helix, which is positioned to potentially transmit a signal to the nucleotide-binding domains. A new ligand-binding site on the surface of P-gp facing the inner leaflet of the membrane is also described, providing vital insights regarding the entry mechanism of hydrophobic drugs and lipids into P-gp. These results represent significant advances in the understanding of how P-gp and related transporters bind and export a plethora of metabolites, antibiotics and clinically approved and pipeline drugs.
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