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Nature's Flexible Keys to Molecular Locks

Por: | 24 de febrero de 2014

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By Zoltán Gáspári, Eötvös Loránd University, Budapest

All life processes can be traced to interactions between molecules. Proteins are some of the most important molecules, fulfilling essential tasks such as digesting food, making muscles move and regulating development. Proteins can interact with other proteins or with different chemical compounds, such as molecules we can smell or taste. Molecular biologists and biochemists have long studied the nature of such interactions in order to understand how life's machinery works at and below the cellular level. Our current understanding allows drug companies to try and design drug molecules specifically to control target proteins involved in disease conditions. However, we are still far from uncovering all the secrets of nature that involve the actions of proteins.

Interactions between proteins have two aspects in apparent contradiction. First, as these molecules are three-dimensional objects, the partners should have complementary shapes in order to be able to make contact with each other. This requirement was formulated as early as the end of the nineteenth century by Emil Fisher's “lock-and-key” theory. In this model the two molecules with well-defined shapes fit each other, ensuring that the two proteins interact (almost) exclusively with each other. On the other hand, researchers investigating the shape of proteins and its role in their function –– that is, structural biologists — have discovered that the shape of proteins can change when they bind with partner molecules, a process called conformational change. Thus, proteins not only have a well-defined shape, but also the ability to change it.

Since the end of the twentieth century, thanks to the achievements of Nobel Prize winners Richard Ernst and Kurt Wüthrich, we have been able to examine proteins in detail using the technique called nuclear magnetic resonance (NMR) spectroscopy. With NMR, we are also able to map the internal dynamics of these molecules — their ability to change their shape, and the amount of change that is possible. NMR has not only confirmed the existence of conformational changes when proteins interact with each other but also revealed that proteins constantly alter their shape.

Until recently, one of the last stands of the rigid lock-and-key model was the action of the so-called canonical protease inhibitors. These are specialized proteins that block proteases, another group of proteins whose task is to cut yet other proteins into pieces for various reasons, such as making them digestible, or activating or degrading them according to the organism's needs. Canonical inhibitors are not expected to cause any conformational changes in the target protease, as they merely need to inhibit its action by binding to the same place where the protein it would normally cut would bind.

My own research conducted with Professor András Perczel at the Institute of Chemistry, Eötvös Loránd University, Budapest, concerns canonical inhibitors isolated from locusts in close collaboration with the team led by Professor László Gráf at the Department of Biochemistry at the same university. These inhibitors were first believed to be quite rigid, based on the observation that they have extra chemical stabilization in their structure, which gives them unusual heat resistance. I have determined their three-dimensional structure by NMR and was able to confirm the presence of their protease binding site. This proved to have a similar shape to that found in other canonical inhibitors, although the rest of the structure is different from many of those. My colleagues at Eötvös University and I have also mapped the internal dynamics of the molecules, and found that contrary to early expectations they are quite mobile. Our most striking result was that their whole structure is as mobile as the protease binding region.

This observation means that the classical lock-and-key model for canonical inhibitors still found in textbooks, and which explains the efficiency of such inhibitors being due to their rigidity, can simply not be fully valid. The interaction cannot be properly described without taking into account the internal mobility of the partners. The presence of flexible rather than rigid keys removes the necessity for the partners to have a completely complementary shape, as the key can adapt to the locks, which might be slightly different from case to case. Moreover, both proteases and their inhibitors have just as flexible a system as any other proteins investigated so far. Thus, flexibility is inherent to probably all of the molecular machines of life. Proper description of internal dynamics is of profound importance in understanding the mechanistic details of interactions, necessary for example for efficient design of drugs in the twenty-first century.

In conclusion, the lock-and-key concept, so useful in the early days of biochemistry, should be interpreted dynamically if we are to understand how nature's flexible keys make molecular locks work.


Zoltán Gáspári
Eötvös Loránd University, Budapest

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