Structural insight into substrate and inhibitor discrimination by human P-glycoprotein

• DOI: 10.1126/science.aav7102
• Publication Date: 2019-02-15T00:15:56Z
• Authors: Amer Alam; Julia Kowal; Eugenia Broude; Igor Roninson; Kaspar P. Locher
• Keywords: 0301 basic medicine; ATP Binding Cassette Transporter, Subfamily B; Binding Sites; Paclitaxel; Hydrolysis; Cryoelectron Microscopy; Mutant Chimeric Proteins; Dibenzocycloheptenes; Antineoplastic Agents, Phytogenic; Substrate Specificity; Mice; 03 medical and health sciences; Adenosine Triphosphate; Cholesterol; Protein Domains; Drug Design; Quinolines; Animals; Humans; Phospholipids; Protein Binding

To transport or not to transport

Therapeutic drug delivery into cells is complicated by membrane proteins like ABCB1 (also termed P-glycoprotein) that shuttle diverse compounds out of cells. Alam et al. determined high-resolution cryo–electron microscopy structures of ABCB1 bound either to a substrate, the cancer drug Taxol, or to the ABCB1 inhibitor zosuquidar. The conformational changes that facilitate drug transport are caused by hydrolysis of adenosine triphosphate (ATP). The structures show that, although Taxol and zosquidar bind to the same site, subtle structural differences lead to altered conformations of the nucleotide binding domains that are responsible for ATP hydrolysis.

Science , this issue p. 753