title: Unidirectional Transport Mechanism in an ATP Dependent Exporter.
abstract: ATP-binding cassette (ABC) transporters use the energy of ATP binding and hydrolysis to move a large variety of compounds across biological membranes. P-glycoprotein, involved in multidrug resistance, is the most investigated eukaryotic family member. Although a large number of biochemical and structural approaches have provided important information, the conformational dynamics underlying the coupling between ATP binding/hydrolysis and allocrite transport remains elusive. To tackle this issue, we performed molecular dynamic simulations for different nucleotide occupancy states of Sav1866, a prokaryotic P-glycoprotein homologue. The simulations reveal an outward-closed conformation of the transmembrane domain that is stabilized by the binding of two ATP molecules. The hydrolysis of a single ATP leads the X-loop, a key motif of the ATP binding cassette, to interfere with the transmembrane domain and favor its outward-open conformation. Our findings provide a structural basis for the unidirectionality of transport in ABC exporters and suggest a ratio of one ATP hydrolyzed per transport cycle.
authors.affiliation: SIB Swiss Institute of Bioinformatics, Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland; Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Biozentrum, University of Basel , Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Seelig
authors.affiliation: SIB Swiss Institute of Bioinformatics, Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland; Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Bernèche