Flipping and other astonishing transporter dance moves in fungal drug resistance

In all domains of life, transmembrane proteins from the ATP-binding cassette (ABC) transporter family drive the translocation of diverse substances across lipid bilayers. In pathogenic fungi, the ABC transporters of the pleiotropic drug resistance (PDR) subfamily confer antibiotic resistance and so are of interest as therapeutic targets. They also drive the quest for understanding how ABC transporters can generally accommodate such a wide range of substrates. The Pdr5 transporter from baker's yeast is representative of the PDR group and, ever since its discovery more than 30 years ago, has been the subject of extensive functional analyses. A new perspective of these studies has been recently provided in the framework of the first electron cryo-microscopy structures of Pdr5, as well as emergent applications of machine learning in the field. Taken together, the old and the new developments have been used to propose a mechanism for the transport process in PDR proteins. This mechanism involves a flippase step that moves the substrates from one leaflet of the bilayer to the other, as a central element of cellular efflux.

Automated summary

This article introduces the role of ABC transporters in fungal antibiotic resistance and discusses the new mechanisms revealed in Pdr5 transporter studies using electron cryo-microscopy structures and machine learning techniques.