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A multidrug efflux pump in motion

Date:
March 13, 2017
Source:
Vanderbilt University Medical Center
Summary:
Researchers have mapped the conformational changes that occur in a protein 'notorious' for pumping chemotherapeutic drugs out of cancer cells and blocking medications from reaching the central nervous system. Their report is an important step forward in understanding - and perhaps one day interfering with - the highly dynamic ABC transporter known as P-glycoprotein.
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Researchers at Vanderbilt University Medical Center have mapped the conformational changes that occur in a protein "notorious" for pumping chemotherapeutic drugs out of cancer cells and blocking medications from reaching the central nervous system.

Their report, published today as a letter in the journal Nature, is an important step forward in understanding -- and perhaps one day interfering with -- the highly dynamic ABC transporter known as P-glycoprotein, said corresponding author Hassane Mchaourab, Ph.D.

A national leader in the study of protein "dynamics," Mchaourab is the Louise B. McGavock Professor in the Department of Molecular Physiology and Biophysics in the Vanderbilt University School of Medicine.

P-glycoprotein is an ATP-binding cassette (ABC) transporter. ABC transporters make up the largest family of transporter proteins and are present in all organisms. They use ATP hydrolysis -- the release of chemical energy stored in ATP molecules -- to traffic a wide variety of molecules across cell membranes.

P-glycoprotein is an ABC transporter of the efflux class that functions to remove molecules from inside the cell, including cytotoxic drugs. In this way it controls the body's pharmacokinetic profile. P-glycoprotein is active in many tissues including the intestine, liver, kidney, placenta and the blood-brain barrier.

P-glycoprotein consists of different components, called domains. Using an electron paramagnetic resonance spectroscopy method called double electron-electron resonance (DEER), the researchers mapped the "shape changes" that allow P-glycoprotein to bind a wide variety of drug-like compounds, move them across the cell membrane and then eject them from the cell.

In particular, the researchers were able to determine how P-glycoprotein's ATP "motor" drives a change in the conformation or spatial orientation of its membrane domain -- the portion of the protein that binds and transports molecules. This conformation change is called "alternating access."

In collaboration with Emad Tajkhorshid, Ph.D., a computational biologist at the University of Illinois at Urbana-Champaign, the researchers generated a model of the specific P-glycoprotein structure that ejects target drugs from the cell.

A culmination of 15 years of effort to understand the mechanistic principles of ABC transporters, their study showed that human P-glycoprotein is structurally and functionally distinct from the well-studied bacterial ABC transporters.

The researchers also discovered an intermediate, "occluded" conformation that occurs after P-glycoprotein binds the target drug but before the drug is ejected from the cell.

This is a key discovery. The intermediate conformation might be the point at which researchers could intervene and prevent P-glycoprotein from pumping chemotherapeutic drugs out of tumor cells before they have had a chance to do their job.

"Now the question is," said Mchaourab, "can we make molecules that exclusively stabilize the occluded confirmation and put the transporter out of commission for a while?"

To that end, the Mchaourab lab is creating a transgenic model of the human P-glycoprotein gene inserted into zebrafish to better understand how the transporter binds different compounds. That information may lead to new ways to block its action.


Story Source:

Materials provided by Vanderbilt University Medical Center. Note: Content may be edited for style and length.


Journal Reference:

  1. Brandy Verhalen, Reza Dastvan, Sundarapandian Thangapandian, Yelena Peskova, Hanane A. Koteiche, Robert K. Nakamoto, Emad Tajkhorshid, Hassane S. Mchaourab. Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein. Nature, 2017; DOI: 10.1038/nature21414

Cite This Page:

Vanderbilt University Medical Center. "A multidrug efflux pump in motion." ScienceDaily. ScienceDaily, 13 March 2017. <www.sciencedaily.com/releases/2017/03/170313135001.htm>.
Vanderbilt University Medical Center. (2017, March 13). A multidrug efflux pump in motion. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2017/03/170313135001.htm
Vanderbilt University Medical Center. "A multidrug efflux pump in motion." ScienceDaily. www.sciencedaily.com/releases/2017/03/170313135001.htm (accessed May 23, 2017).

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