There is a graphical abstract. Credit: DOI: 10.1038/s41589-021-00936-x
The inner-workings of a two-stage "molecular motor" in the cell are revealed by researchers at the University of Arizona.
Their findings, which were reported recently in the journal Nature Chemical Biology, will aid the search for drugs that can turn off the ABC transporter. Efforts to block the human version of the transporter that enables tumors to become resistant to chemotherapy are informed by them.
"We're asking the question, how did nature design this particular motor, how did it work?" said Mchaourab, co-corresponding author of the paper with Tomasiak.
He said that understanding how transporters work is essential to developing drugs that block them.
Mchaourab is the Louise B. McGavock Professor in the Department of Molecular Physiology & Biophysics at Vanderbilt. Tomasiak is an assistant professor at the University of Arizona.
According to the U.S. Centers for Disease Control and Prevention, antibiotic-resistantbacteria and fungi are responsible for more than 35,000 deaths in the US each year.
The multi-drug ABC exporter is a primary vehicle for resistance. ABC exporters use the release of chemical energy stored in ATP molecule to traffic a wide variety of molecule across cell membranes.
ABC exporters can turn around and expel toxic chemicals by using the power of the ATP energy. This survival tactic can prove fatal to the human host they have invaded.
In collaboration with researchers at the University of Illinois at Urbana-Champaign, Mchaourab's team used a technique called electron paramagnetic resonance (EPR) spectroscopy to identify previously unreported changes in the shape of the ABC exporter from a bacterium called Bacillus subt.
They proposed that the transition between inward and outward-facing conformations of the exporter is driven by the power of the ATP. After binding the antibiotic, the exporter "turns around" so it can get out of the cell.
The motion is caused by the conversion of chemical energy into mechanical energy by the asymmetrical and sequential binding of two ATP molecule to different parts of theProtein complex. Asymmetrical binding drives change.
To prove their theory, the researchers had to take a picture of the change. They turned to another resource, which allows measurement of atomic distances at minus 320 degrees Fahrenheit.
The studies were done at the Pacific Northwest Center. The studies revealed for the first time an inward-facing structure with two drug molecules bound asymmetrically.
Mchaourab said they had evidence in the form of indirect evidence. We can say with atomic detail what is happening.
He said that the intermediate conformation suggests that drugs could be designed to "trapping" the antibiotic from the exporter.
Tarjani M. Thaker and his team have shown that a drug binding in an ABC transporter is asymmetric. The DOI is 10.1038/s41589-021-00936-x.
Nature Chemical Biology has a journal.
The study explores howbacteria become drug resistant.
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