How can multidrug efflux pumps have poly-substrate binding affinity? Some can bind both metals and antibiotics! What's the common denominator of the substrates? Thanks!
Hello, maybe you can find your answers in the link below.
Hoping to be helpful. Greeting,
Ramona.
http://www.sciencedirect.com/science/article/pii/S0006291X14009711
Dear Joe
This depend on type of efflux pump,for example QacR can bind to various structurally dissimilar compounds that are the substrates of QacA efflux transporter, such as rhodamine 6G, ethidium and crystal violet . Structure of QacR bound simultaneously with two or more different drugs such as ethidium (Et) and proflavin (Pf) has been resolved, and it reveals the regulatory mechanism of QacR in response to structurally different compounds.
Best regrades
Mohammed F. Al Marjani
Thanks for the article, Ramona. I think I've seen this one before, though. It certainly states that efflux pumps can bind various substrates, but maybe I missed where it indicates what interactions enable this poly-substrate binding. I'll take another look.
Thanks to you, too, Mohammed. When the structure of QacR was resolved, did the researchers determine why it's able to bind structurally different compounds, like Et and Pf?
Depending on the specific classes they belong to, efflux pumps are either single-component transporters or multiple-component systems containing not only an inner membrane transporter, but also an outer membrane channel and a periplasmic adaptor protein, such as the RND type efflux pumps. Owing to their tripartite composition which allows direct extrusion of various drugs from cytosol or periplasmic space to the outside of bacterial cells, RND family pumps have been found to be associated extensively with clinically significant antibiotic resistance, such as AcrB in Escherichia coli and Salmonella typhimurium and MexB in Pseudomonas aeruginosa.
As far as I understand about multidrug efflux pumps, the natural substrate of these pumps (specially RND) has not been proven yet which brings to a classic question that what does these pumps do in natural environment? The multidrug pumps like RND, changes its conformation based on the type of substrates attached to its amino acid residues. Change in conformation allow these pumps to form a working channel and efflux the substrate out. Just for an example, MexXY pump, which is a RND pump complex of P. aeruginosa, is highly expressed in nitrosative stress condition but once they are over expressed they can pump out rare RND substrates like aminoglycosides making bacteria multidrug resistance. People are trying to understand the binding pocket of these pumps and their role in pump functional conformation. It has been proposed that different sets of amino acids are involved in binding to different substrates which explains the multidrug specificity of these pumps.
In conclusion, the natural substrates of most of the efflux pumps are not yet known which makes it hard to predict the range of substrates that can be taken by them.
It is very active area of research and one of the efficient way to target multidrug resistance in bacteria. There are many people working on it along with our lab as well.
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