Conformational Motion Of The ABC Transporter MsbA Induced By ATP Hydrolysis

Main Category: Biology / Biochemistry
Also Included In: Infectious Diseases / Bacteria / Viruses;  Cancer / Oncology
Article Date: 08 Oct 2007 - 19:00 PST

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In a new study published in the open-access journal PLoS Biology, Peter Borbat, Hassane Mchaourab, and colleagues find that clinical multidrug resistance in the treatment of bacterial and fungal infections and cancer chemotherapy can result from the expression of pumps that extrude toxic molecules from the cell. A subclass of these pumps - ATP binding cassette (ABC) transporters - use energy from ATP to remove a wide range of molecules. MsbA is a conserved ABC transporter from gram negative bacteria with sequence similarity to human multi-drug ABC transporters. MsbA flips the building block of the outer membrane, lipid A, across the inner membrane.

The input of ATP energy occurs at two dedicated nucleotide binding domains (NBDs) whose configuration in intact transporters is controversial. They determined the amplitude of MsbA conformational motion that couples energy expenditure to substrate movement across the membrane. Using molecular probes introduced into the protein sequence, they found that ATP hydrolysis fuels a relative motion of the NBDs close to 30 Å.

The movement of the NBDs is coupled to reorientation of the chamber which binds the lipid substrate from  cytoplasmic-facing to extracellular-facing through large amplitude motion on either side of the transporters. In addition to revealing the structural mechanics of transport, these results challenge current models deduced from studies of substrate-specific ABC importers that envisions the two NBD in contact throughout the ATP hydrolysis cycle.

Citation: Borbat PP, Surendhran K, Bortolus M, Zou P, Freed JH, et al (2007) Conformational motion of the ABC transporter MsbA induced by ATP hydrolysis. PLoS Biol 5(10): e271. doi:10.1371/journal.pbio.0050271
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