4Q9H

P-glycoprotein at 3.4 A resolution

Summary for 4Q9H

• Entry DOI: 10.2210/pdb4q9h/pdb
• Related: 4Q9I 4Q9J 4Q9K 4Q9L
• Descriptor: Multidrug resistance protein 1A (1 entity in total)
• Functional Keywords: membrane protein, transporter, hydrolase
• Biological source: Mus musculus (mouse)
• Cellular location: Cell membrane; Multi-pass membrane protein: P21447
• Total number of polymer chains: 1
• Total formula weight: 141919.95

Authors

McGrath, A.P.,Szewczyk, P.,Chang, G. (deposition date: 2014-05-01, release date: 2015-03-04, Last modification date: 2024-02-28)

Primary citation

Szewczyk, P.,Tao, H.,McGrath, A.P.,Villaluz, M.,Rees, S.D.,Lee, S.C.,Doshi, R.,Urbatsch, I.L.,Zhang, Q.,Chang, G.
Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein.
Acta Crystallogr.,Sect.D, 71:732-741, 2015

PubMed 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.

PubMed: 25760620
DOI: 10.1107/S1399004715000978

Experimental method

X-RAY DIFFRACTION (3.4 Å)