4q9l
P-glycoprotein cocrystallised with QZ-Phe
Structural highlights
FunctionMDR1A_MOUSE Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.[1] Publication Abstract from PubMedP-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. Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein.,Szewczyk P, Tao H, McGrath AP, Villaluz M, Rees SD, Lee SC, Doshi R, Urbatsch IL, Zhang Q, Chang G Acta Crystallogr D Biol Crystallogr. 2015 Mar 1;71(Pt 3):732-41. doi:, 10.1107/S1399004715000978. Epub 2015 Feb 26. PMID:25760620[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
