Abstract
SummaryDrugs and certain proteins are transported across the membranes of Gram-negative bacteria by energy-activated pumps. The outer membrane component of these pumps is a channel that opens from a sealed resting state during the transport process. We describe two crystal structures of the Escherichia coli outer membrane protein TolC in its partially open state. Opening is accompanied by the exposure of three shallow intraprotomer grooves in the TolC trimer, where our mutagenesis data identify a contact point with the periplasmic component of a drug efflux pump, AcrA. We suggest that the assembly of multidrug efflux pumps is accompanied by induced fit of TolC driven mainly by accommodation of the periplasmic component.
Highlights
Resistance to drugs is an obstacle in the treatment of infections by pathogenic bacteria
The pump comprises an outer membrane channel, an inner membrane protein that transduces electrochemical energy, and a bridging protein that links the transmembrane components through protein-protein interactions in the periplasm (Thanassi and Hultgren, 2000; Delepelaire, 2004)
Channel Opening in a Bacterial Efflux Pump well as the wild-type TolC in conferring partial resistance to the antibiotic novobiocin that is extruded by the efflux pump composed of TolC, AcrB, and AcrA (Table 1)
Summary
Resistance to drugs is an obstacle in the treatment of infections by pathogenic bacteria. In Gram-negative bacteria, these transporters take the form of three-component efflux pumps that span the inner and outer membranes and the interstitial periplasm. The pump comprises an outer membrane channel, an inner membrane protein that transduces electrochemical energy, and a bridging protein that links the transmembrane components through protein-protein interactions in the periplasm (Thanassi and Hultgren, 2000; Delepelaire, 2004). Analogous multicomponent pumps have been identified that export proteins such as toxins and adhesion factors, and for such pumps the inner membrane component is typically a member of the ATP-binding cassette transport family (Nikaido and Zgurskaya, 2001; Dawson and Locher, 2006). Crystal structures are available for representatives of all three components of tripartite efflux pumps (Koronakis et al, 2000; Murakami et al, 2002; Akama et al, 2004), but the structure of the ternary assembly is presently unknown
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