Open AccessSnapshots of ligand entry, malleable binding and induced helical movement in P‐glycoprotein
Author(s) -
Szewczyk Paul,
Tao Houchao,
McGrath Aaron P.,
Villaluz Mark,
Rees Steven D.,
Lee Sung Chang,
Doshi Rupak,
Urbatsch Ina L.,
Zhang Qinghai,
Chang Geoffrey
Publication year - 2015
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s1399004715000978
Subject(s) - transporter , ligand (biochemistry) , atp hydrolysis , p glycoprotein , atp binding cassette transporter , conformational change , chemistry , transmembrane protein , binding site , biochemistry , nucleotide , plasma protein binding , biophysics , transmembrane domain , stereochemistry , receptor , biology , enzyme , atpase , antibiotics , gene , multiple drug resistance
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.