| Structure and Function Relationships of Proteins |
The three-dimensional structure of a protein defines not only its size and shape, but also its function. One characteristic that affects function is the hydrophobicity of a protein, which is determined by the primary and secondary structure. For example, let's look at membrane proteins. Membranes contain large amounts of lipids, which are notoriously hydrophobic (water and oil don't mix). The membrane-spanning regions of membrane proteins are typically alpha helices, made of hydrophobic amino acids. These hydrophobic regions interact favorably with the hydrophobic lipids in the membrane, forming stable membrane structures.
Hemoglobin is a soluble protein - found in the cytoplasm of red blood cells as single molecules - which bind oxygen and carry it to the tissues. In sickle cell anemia, a mutation in the beta-globin protein of the red blood cell increases its hydrophobicity and causes the mutant protein molecules to stick to each other, avoiding the aqueous environment. Chains of hemoglobin change the shape of the red blood cell from round to a sickle shape, which causes the cells to collect in narrow blood vessels.
The folding of a protein allows for interactions between amino acids that may be distant from each other in the primary sequence of the protein. In enzymes, some of these amino acids form a site in the structure that catalyzes the enzymatic reaction. This site, called the active site of the enzyme, has amino acids that bind specifically to the substrate molecule, also called a ligand (Fig. 2). In a similar manner, certain sites in cell receptor proteins bind to specific ligand molecules that the receptor recognizes.
Alterations in amino acids that may be distant from each other in the primary sequence can lead to changes in folding. It may also cause changes in chemical interactions among amino acids at the active site, which alter the enzyme activity or binding of the ligands to receptor proteins. Binding of ligands to an active site requires specific amino acids. Therefore, an active site in a new enzyme that belongs to the same family as a known enzyme can usually be identified by its similarity to the active site of the known protein. Computer programs can use the information from a database of known enzymes to predict the active site of a new protein using a template-based method, similar to that described above for determining the three-dimensional structure of a protein. Once the program has identified the potential ligand-binding sites, other programs can test the fit and the binding ability of thousands of possible ligand molecules - even theoretical ligands that may not yet exist. This has tremendous possibilities for the design of new drugs, particularly for cancer therapy.