Molecules on the timeline

A method developed by the Institute's scientists for dynamic monitoring of enzymes in action is used to plan and design new and effective drugs

From the right: Ariel Solomon, Barak Akabiov and Prof. Irit Sagi. delusional
A deep understanding of the biophysical characteristics of enzymes, and the ability to follow precisely, and in real time, their mode of action, were considered for years tasks that could only be achieved in many years. But as happens in many cases, the reality progressed faster than all the predictions. Thus, a method for dynamic documentation of processes that take place in an enzyme during its activity, developed by Prof. Irit Sagi from the Department of Structural Biology, in the Faculty of Chemistry at the Weizmann Institute of Science, and the members of the research group she heads, is currently used as a powerful tool in the planning and development processes of new drugs.
Enzymes are proteins that function as complex molecular machines, operating at breakneck speed. In order to understand their physical characteristics, which dictate their mode of activity, it is necessary to identify, in addition to their three-dimensional spatial structure, the changes that occur in their structure during their activity (these dynamic changes give enzymes their great efficiency). This is exactly what Prof. Sagi and her group members did. They developed a method for dynamic documentation of processes and structural changes that take place in an enzyme molecule during its activity, which contributes to a more accurate understanding of the chemical reaction mechanism in the studied enzyme. This understanding may help in designing drugs that will inhibit the enzyme and control the extent of its activity. These new drugs will be particularly targeted, and will target individual atoms or certain structural processes that occur in the enzyme molecule. This focus may greatly reduce the side effects of future drugs that will be designed using this method.
The new method allows scientists to detect the movement of individual atoms that change their place in the enzyme molecule. To do this, they freeze the process at certain stages, and use advanced methods from the field of chemical-structural analysis to determine the exact molecular arrangement that exists at each stage of the enzyme's activity.
The members of Prof. Sagi's research group began to use the new research tool they had developed on the molecules of a certain enzyme, the "suspect" of being involved in many diseases, starting with multiple sclerosis, and ending with certain types of cancer. This enzyme, called "TNF alpha convertase", is a member of the group of protease enzymes (which cut proteins). One of its functions is to cut a protein called "pro-TNF alpha", and release it from its attachment to the cell membrane. The released protein can migrate in the body and perform various activities. A certain amount of such proteins is necessary for various vital processes, but too much - resulting from overactivity of the releasing enzyme - may cause malfunctions and open the processes leading to the development of diseases. To prevent this unwanted process, many scientists try,
In different parts of the world, to develop drugs that will bind to the active site of the enzyme molecules and inhibit their activity. However, despite multiple efforts, scientists have not been able to develop a drug that would inhibit the enzyme - without causing devastating, and sometimes even fatal, side effects.
Over the years, it became clear that the reason for the failures of these efforts is the great structural similarity between the enzyme TNF alpha convertase, and other enzymes from the protease family, which perform a long series of vital activities in the body. This structural similarity meant that drug molecules, which were based on the structural features that describe a single state of the enzyme molecule, also attached to the other enzymes of the protease family, and inhibited them as well. Inhibiting the activity of the other enzymes damaged various vital activities, and caused the negative side effects.
Here, more or less, Prof. Sagi and the members of the research group she heads came into the picture. Using the dynamic tracking method they developed, they were able to track the activity of the enzyme, and record any changes that occurred in it at millisecond intervals. Thus, in the first stage, they provided direct evidence for the way the reaction mechanism works, which was controversial for many years.
In the second stage, they discovered that when the enzyme approaches the protein it is cutting, it is literally "excited towards it": the first contact of the protein with the enzyme molecule causes a change in the structure of the enzyme and significant electronic changes of a single zinc atom located in the active site of the enzyme molecule. This characteristic structural change is unique to the TNF alpha convertase enzyme, so drugs aimed at blocking this structural process will act selectively and precisely, will not bind to other enzymes, and therefore will not cause negative side effects. The findings of this study were recently published in the journal "Records of the American Academy of Sciences", PNAS.
The ability to identify dynamic structural characteristics unique to the molecules of many other enzymes, at different stages of their activity, may be a powerful tool for planning and designing a new generation of drugs that will work very efficiently, and without side effects. Various pharmaceutical companies have already expressed interest in the dynamic-structural tracking method and the new research approach.