Cryo-EM structures reveal distinct mechanisms of inhibition of human multidrug transporter ABCB1

A recently published “PNAS” paper by the Locher group (IMBB) demonstrates how ABCB1 inhibitors bind in pairs and can block the function of the transporter by interacting with structural features that are important for its transport function.

Locher paper PNAS
Molecules that only occupy the central cavity behave like substrates, even if they belong to the inhibitor family. Inhibitors can bind in pairs and occupy not only the drug-binding pocket, but extend into the vestibule and/or access tunnel.

ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood.

The researchers determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. They found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that were termed the “access tunnel.” This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. The structural data will also help the development of more potent and selective ABCB1 inhibitors.

Link to the paper in PNAS.

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