Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Molecular spies illuminate drug resistance proteins

13.05.2005


Intricate details about a cellular protein, worked out by Vanderbilt University Medical Center scientists, may aid in the design of drugs that cells find ’irresistible.’



Resistance to antibiotics and chemotherapeutic agents is a growing medical concern. Multidrug resistance (MDR), in which cells are resistant to a number of unrelated drugs, is a particular problem in cancer chemotherapy. One mechanism that underlies MDR results from a normally beneficial cellular process. Multidrug transporters, proteins embedded in the membrane of every cell from the most humble bacterium to the most sophisticated human cell, provide an important, nonspecific form of protection by purging toxic compounds from the cell. "Multidrug transporters are a part of a defense mechanism universal to all organisms that allows them to remove cytotoxic molecules out of the cytoplasm," said Hassane Mchaourab, Ph.D., associate professor of Molecular Physiology and Biophysics, at Vanderbilt University Medical Center, the senior author on the study.

But, in doing so, they contribute to cells becoming resistant to some therapeutic drugs, most notably antibiotics and chemotherapy drugs. In the May 13 issue of Science, Vanderbilt University Medical Center scientists reveal details about the structure and function of a multidrug transporter called MsbA that may help advance the design of new antibiotics and chemotherapy drugs that will be able to evade these transporters.


The first step in designing drugs that can defy these proteins is determining the structure and function of these transporters. The basic structure of MsbA had previously been determined through crystal structure analysis, which provides a visual representation of an individual protein. However, a static model, which a crystal structure provides, reveals little about the way that protein functions. "Crystal structure gives you a snapshot, but what you really want is a movie," Mchaourab said. Using a sophisticated molecular espionage technique called spin labeling, Mchaourab and colleagues attempted to make that movie.

First, they isolated MsbA protein from E. coli and inserted the pure protein into liposomes, synthetic membranes that mimic the protein’s natural home in the cell membrane. Then, they sent in the spies. "The basic strategy (in spin labeling) is to introduce probes into the protein, sort of molecular spies, and then receive signals from these molecular spies and decode them to describe the local structure around them." "By moving the spy across the entire protein structure, you are able to get a picture, a reasonable, medium resolution structure of the protein. Even more important, you can watch the change in the structure during the functional cycle."

While their structure looked similar to the previous crystal structures except in functionally important details, the spies were able to reveal something the crystal structures couldn’t – the opening and closing of the transporter in response to energy expenditure. Multidrug transporters like MsbA pump molecules out of the cell using the energy released by the reaction of ATP (adenosine triphosphate), the cell’s ’fuel’ source, and water. This characteristic puts them in a special class of transporters, called ABC (ATP-binding cassette) transporters.

The researchers saw that ATP binding to the protein caused the chamber, a pore-like hole in the protein, to close from the inside of the cell outwards. This traps a molecule, like a drug or toxin, inside the chamber. At about the same time, the external part of the chamber begins to open, which allows the trapped molecule to be expelled from the cell. These findings provide an important first step towards combating drug resistance in humans and infectious organisms. Humans have 47 types of multidrug ABC transporters, the most prominent and notorious being P-glycoprotein, which is responsible for resistance to chemotherapy.

Since the MsbA protein used in this study is about 35 percent identical to the P-glycoprotein found in humans, information gained about it should also apply to transporters involved in human drug resistance. Additionally, MsbA is also the only ABC transporter in E. coli that is essential for the survival of the organism, which makes it a possible therapeutic target. "The motivation for this work is to understand where the substrate binds and how it moves across so that one can start thinking about designing inhibitors of these molecules," Mchaourab said. "Whether it’s resistance to infectious diseases or resistance to chemotherapy, the goal is to silence these proteins by designing inhibitors that bind tighter than the chemotherapeutic drugs or the antibiotics."

The research was supported by a Vanderbilt Discovery Grant. Other Vanderbilt authors on the paper were Jinhui Dong, a graduate student and first author, and Guangyong Yang, research assistant in the Mchaourab lab.

Clinton Colmenares | EurekAlert!
Further information:
http://www.vanderbilt.edu

More articles from Life Sciences:

nachricht What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Simple processing technique could cut cost of organic PV and wearable electronics

06.12.2016 | Materials Sciences

3-D printed kidney phantoms aid nuclear medicine dosing calibration

06.12.2016 | Medical Engineering

Robot on demand: Mobile machining of aircraft components with high precision

06.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>