Distinct allosteric mechanisms of first-generation MsbA inhibitors

Distinct mechanisms to block transporters Transmembrane ATP-binding cassette (ABC) transporters are crucial cellular machines that move molecules small and large across membranes. In Gram-negative bacteria, outer membrane biogenesis is aided by an ABC transporter called MsbA, which flips lipopolysaccharide from the inner face of the cell membrane to the periplasmic face. Thélot et al . determined structures of two first-generation inhibitors bound to MsbA, TBT1 and G247, and found that they have distinct binding modes. Unlike most inhibitors, TBT1 triggers unproductive ATPase activity and induces a conformation similar to substrate bound. These structures will provide valuable information for the design of potential antimicrobial drugs. The authors have already identified a new lead compound from virtual screening based on the TBT1-induced conformation. —MAF