Molecular Microbiology and Structural Biochemistry, UMR 5086 CNRS/Univ. Lyon, IBCP, Lyon
Insights into how the conformational changes are relayed between the ATP- and the drug‐binding sites in a multidrug ABC transporter
Multidrug efflux transporters are a plague in the antibiotic resistance era as they allow pathogenic bacteria to evade most of current therapies. Some of these 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(s), located ~ 40 Å apart from each other, is achieved remains unsolved.
Using an archetypical multidrug transporter from Bacillus subtilis, BmrA, and combining 3D structure with biochemical and biophysical techniques (i.e. NMR and HDX-MS), 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- to the drug-binding sites, thereby allowing drug efflux.
- C. Orelle, K. Mathieu & J.-M. Jault Res Microbiol (2019) 170, 381-391 “Multidrug ABC transporters in bacteria”
- D. Lacabanne, C. Orelle, L. Lecoq, B. Kunert, C. Chuilon, T. Wiegand, S. Ravaud, J.-M. Jault, B. H. Meier & A. Böckmann Commun Biol (2019) 2, 149 “Flexible-to-rigid transition is central for substrate transport in the ABC transporter BmrA from Bacillus subtilis”.
- K. Mathieu, W. Javed, S. Vallet, C. Lesterlin, M.-P. Candusso, F. Ding, X. N. Xu, C. Ebel, J.-M. Jault & C. Orelle Sci Rep (2019) 9, 2654 “Functionality of membrane proteins overexpressed and purified from E. coli is highly dependent upon the strain”.
- S. Mehmood, C. Domene, E. Forest & J.-M. Jault Proc Natl Acad Sci USA (2012) 109, 10832-10836, “Dynamics of a bacterial multidrug ABC transporter in the inward and outward facing conformations”.
Contact: Julien Marcoux (Julien.Marcoux@ipbs.fr)
For IPBS colleagues, the seminar will take place in the seminar room (max 20 people). Due to the COVID-19-related situation, the seminar is NOT open to persons outside the IPBS.
Link to attend the seminar: https://meet.starleaf.com/4278587390/app
10:00 - 11:00
Seminar room - IPBS | Hybrid conference