Snapshots of ligand entry, malleable binding and induced helical movement in P‐glycoprotein. (1st March 2015)

• Record Type: Journal Article
• Authors: Szewczyk, Paul; Tao, Houchao; McGrath, Aaron P.; Villaluz, Mark; Rees, Steven D.; Lee, Sung Chang; Doshi, Rupak; Urbatsch, Ina L.; Zhang, Qinghai; Chang, Geoffrey
• Is Part Of: Acta crystallographica. Volume 71:Part 3(2015:Mar.)
• Page Start: 732
• Page End: 741
• Publication Date: 2015-03-01
• Subjects: Biomolecules -- Structure -- Periodicals; Physical biochemistry -- Periodicals; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; 572
• DOI: 10.1107/S1399004715000978
• Languages: English
• ISSNs: 0907-4449

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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.</p> </abstract>