Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1

• DOI: 10.1073/pnas.1717044115
• Publication Date: 2018-02-13T17:47:28Z
• Authors: Amer Alam; Raphael Küng; Julia Kowal; Robert A. McLeod; Nina Tremp; Eugenia V. Broude; Igor B. Roninson; Henning Stahlberg; Kaspar P. Locher
• Keywords: Cyclic nucleotide-binding domain

The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette that has a key role in protecting tissues from toxic insult and contributes to extrusion cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free trapped by engineered disulfide cross-link between nucleotide-binding domains (NBDs) bound antigen-binding fragment human-specific inhibitory antibody UIC2 third-generation inhibitor zosuquidar. Our reveals occluded conformation with central, enclosed, inhibitor-binding pocket lined residues all transmembrane (TM) helices ABCB1. spans almost entire width lipid membrane occupied exclusively two closely interacting zosuquidar molecules. external, conformational epitope facilitating binding also visualized, providing basis for its inhibition substrate efflux. Additional structures suggest concerted movement TM both halves transporters associated closing NBD gap, as well binding. results define distinct recognition interfaces agents, which may be exploited therapeutic purposes.