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First structure of transporter enzyme family is solved

01.08.2003


Finding will aid drug design to combat depression, stroke and diabetes. Scientists are a step closer to understanding how essential nutrients, vitamins and minerals are ferried into cells.



For the first time, a member of the Major Facilitator Superfamily (MFS) of transport proteins, found in almost every form of life, has been visualised by researchers from Imperial College London and the University of California, Los Angeles.

Reporting in Science today, the researchers reveal the structure of lactose permease, the enzyme in Esherichia coli that helps pump lactose, the major sugar in milk, into cells. Using the structure data, the researchers propose a possible mechanism of action, which is likely to be common among other transport proteins in this family.


Professor So Iwata of Imperial’s Centre for Structural Biology and senior author of the paper explains: "Membrane transport proteins play major roles in depression, stroke and diabetes. Unravelling their structure is critical not only for understanding how we function, but also to improve drug design. Indeed, two of the most widely prescribed drugs in the world, Prozac and Prilosec, act through these proteins.

"The three-dimensional structure of lactose permease gives us our first real picture of how the family of enzymes work. For example, in humans the MFS transporter GLUT4 is responsible for increased glucose uptake in response to insulin stimulation, which has important implications for diabetes. Using the structure of lactose permease we can model GLUT4 and design drugs to control glucose uptake."

Membrane transport proteins play a crucial role in maintaining the selective internal environment of cells. They act as gatekeepers by controlling the entry of nutrients and the exit of waste products. But only four transport protein structures are presently known, compared with over 30,000 soluble protein structures, because they are notoriously difficult to crystallise.

Professor Iwata’s Laboratory of Membrane Protein Crystallography is one of a small number around the world that focuses on determining the three-dimensional structure of membrane embedded proteins.

By combining expertise with Professor Ron Kaback of the University of California, who has been working on lactose permease for 30 years, they have finally solved the structure of this important protein.

Previous biochemical studies had identified six sites within the genetic code of lactose permease that are thought to be crucial to transportation. Using the latest X-ray crystallography techniques, the researchers were able to visualise how lactose permease binds to sugar.

"We have been able to pinpoint areas in the genetic code critical for binding and transport of sugar, which are consistent with information derived from biochemical studies, "said Professor Iwata.

By combining the structural data with previous findings the researchers propose a mechanism of enzyme action.

"Computer simulations show that the enzyme works in a surprisingly simple way. The enzyme is literally gate-keeping. Usually the gate is open towards the outside of the cells and various substances can reach the sugar-binding pocket in the middle of the enzyme, embedded in the cell membrane.

"Only when the enzyme identifies lactose does the other gate, connected to the inside of the cell, open and let the sugar go through. This process is driven by energy called the ’proton motive force’ and should be common among membrane transport proteins."

Professor Iwata added: "Only 40 years ago the idea that genes could be specifically turned on or off in response to different environmental conditions was revolutionary. It was studies in E. coli that showed the bacterial cellular machinery needed to digest lactose is only activated when glucose is not available. Now we have a detailed molecular understanding of how lactose permease contributes to this process."

Judith H Moore | EurekAlert!
Further information:
http://www.imperial.ac.uk

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