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X-ray and Cryo-EM structures of the multidrug transporter BmrA as missing links in the ABC exporters multi-equilibrium mechanism

Vendredi 27 septembre 11:00 - Duree : 1 heure
Lieu : Salle des séminaires de l’IBS - 71, avenue des Martyrs - Grenoble

Orateur : Vincent CHAPTAL (Institut de biologie physico-chimique, Lyon)

Drug resistance is a major health concern, with strong clinical implications in anti-cancer, anti-bacterial and anti-fungal therapies. Several molecular mechanisms will result in drug resistance, mostly sharing a common simple idea ; the therapeutic molecule needs to reach its cellular target to be efficient. Cells have devised several strategies to evade the lethal effects of the therapeutic molecules, for example by modifying the target, removing the target, or preventing the molecule to penetrate inside the cell, etc... ABC transporters are a large family of membrane proteins that belong to the later case, being in charge of detoxifying the cell by expelling toxic compounds through the plasma membrane ; it thereby decreases the molecule concentration bellow cytotoxic levels, which prevents its activity. It is described that they follow a transport cycle, obeying the alternating access mechanism, utilizing the energy of ATP binding and hydrolysis to transport their substrates. We have solved the X-ray and Cryo-EM structures of the B. subtilis multidrug transporter BmrA in two related, yet different, transient outward-facing states (Figure 1). These structures are a missing link between many structures of homologs available today, and provide a detailed molecular movie of drug release. We conducted molecular dynamics simulations that confirm predictions from the structures, and reveal conformational changes post-substrate translocation. Together, these results call for a change of view on how ABC transporters transport their substrates, not through a transport cycle.

Contact : ibs.seminaires@ibs.fr

Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (IBS)
Nature évènement : (Séminaire)
Evènement répétitif : (Séminaire IBS)
Site de l'évènement : Polygone scientifique

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