Drug discovery is a high-tech matching game. Scientists at pharmaceutical companies isolate a particular protein, try to find out as much as possible about it, and then hit it with a molecule that changes its functioning. Once they think they know the shape of the protein, they screen thousands of compounds trying to find the right "key" for the protein "lock".
Now, a new study from the Argonne National Laboratories published in the January 11 issue of the Journal of Molecular Biology, has strengthened the evidence that the shape of that lock can change in different environments. Proteins are biological Transformers. As the lead researcher, Argonne biochemist Lee Makowski said in a statement, "Proteins are not static, they're dynamic."
Depending on the concentration of the proteins -- whether or not they are crowded together or able to hang loose -- the proteins take on different configuration. The more space they have, the more configurations they can take on. The finding sheds light on why drug development is so difficult. Even if researchers can find a drug that works when the protein is in its standard configuration, environmental changes could cause the protein to reshape itself, and render the drug ineffective.
The task is further complicated because protein shapes are incredibly complex. Take a look at the proteins to the left. They are the Molecules of the Month from the
Research Collaboratory for Structural Bioinformatics and happen to help regulate circadian rhythm in a bacterium.
The main technique for finding protein shapes is called X-ray crystallography, which as the name suggests, depends on crystallized proteins, not their in-vitro forms. After scientists grow the crystals (which most of them call an "art"), they are shot through with a powerful X-ray, which creates a diffraction pattern that is used to compute a model of the protein.
X-ray crystallography, however, yields fuzzy results where the proteins are moving. As Baylor and Rice professor Jianpeng Ma, said in 2007, "It is perhaps ironic that current techniques give us the fuzziest detail in the regions where we desire the most clarity."
The good news is that as scientists discover more about how and why proteins move (which Ma is working on), they will be able to more accurately model protein behavior, which could help pharmaceutical companies develop more effective drugs with less side effects. (Side effects, after all, are just the impact of a molecule key getting stuck in the wrong lock, i.e., an unintended protein).
Images: 1. In this false color rendering of an E. Coli cell, blue proteins crowd around purple ribosomes. Credit: Argonne National Laboratory. 2. Kai proteins from cyanobaceria. Credit: RCSB.
