Format

Send to

Choose Destination
Acta Crystallogr D Biol Crystallogr. 2015 Mar;71(Pt 3):732-41. doi: 10.1107/S1399004715000978. Epub 2015 Feb 26.

Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein.

Author information

1
Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92023, USA.
2
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Skaggs School of Pharmacy and Pharmaceutical Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of California, La Jolla, CA 92023, USA.
5
Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
6
Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.

Abstract

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.

KEYWORDS:

P-glycoprotein

PMID:
25760620
PMCID:
PMC4356375
DOI:
10.1107/S1399004715000978
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for International Union of Crystallography Icon for PubMed Central
Loading ...
Support Center