Jean-Michel Jault: A conformational relay between the ATP- and the drug‐binding site of a multidrug ABC transporter
Speaker: Jean-Michel Jault, Research Director of the CNRS, Molecular Microbiology and Structural Biochemistry, IBCP CNRS/Université de Lyon
Lutz Schmitt, Biochemie I, Heinrich Heine Universität Düsseldorf
Joachim Geyer, Institut für Pharmakologie und Toxikologie, Justus-Liebig-Universität Gießen
Organizers: Study Group Biomembranes
Multidrug efflux transporters are a plague in the antibiotic resistance mechanisms as they allow pathogenic bacteria to evade most of current therapies. Some of these bacterial multidrug transporters use the energy coming from ATP hydrolysis to efflux antibiotics and they belong to a very large protein superfamily known as the ABC (“ATP-Binding Cassette”) transporters. Despite the flood of 3D structures in the recent years, the intimate mechanism allowing drug efflux is still poorly understood. In particular, how the coupling between the ATP-binding site and the drug-binding site, located ~ 40 Å apart from each other, is achieved remains unsolved.
Using an archetypical multidrug transporter from Bacillus subtilis, and combining 3D structure with biochemical and biophysical techniques, we have identified a ‘conformational relay’ in the nucleotide-binding domain. This relay is an essential feature to propagate the conformational changes from the ATP-binding site to the drug-binding site, thereby allowing drug efflux.