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PDBsum entry 4q9h
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References listed in PDB file
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Key reference
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Title
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Snapshots of ligand entry, Malleable binding and induced helical movement in p-Glycoprotein.
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Authors
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P.Szewczyk,
H.Tao,
A.P.Mcgrath,
M.Villaluz,
S.D.Rees,
S.C.Lee,
R.Doshi,
I.L.Urbatsch,
Q.Zhang,
G.Chang.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2015,
71,
732-741.
[DOI no: ]
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PubMed id
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Abstract
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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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