The Shape of the Messenger: Using Protein Structure Information to Design Novel Cytokine-based Therapeutics

The cloning and mass production of recombinant cytokine proteins opened a new world of treatment possibilities. While some cytokines, including several haematopoietic factors and interferons, are now used routinely in the clinic, there are still many problems with side effects. These are due to the many different activities of cytokines on different cell populations. In some cases, activities responsible for side effects have been attributed to discreet areas of the proteins and “structure driven design” can be used to generate novel proteins with better clinical profile. In other cases, structural alterations can enhance activity by increasing serum half-life. This review summarizes the structures of cytokines and their receptor complexes deposited in the Protein Data Base (PDB) and introduces the other articles in this issue on structure-driven design of cytokines for therapy. Cytokines fall into only a few structural classifications. Most of the growth regulatory cytokines including serum factors, growth hormone, haematopoietic growth factors, colony stimulating factors, erythropoietin, IL-3, IL-2 and interferons, are four or five helix bundles. Factors which primarily induce inflammatory responses, including TNF, lymphotoxin and IL-1, form β-barrel structures that resemble the FGF family. Chemokines and factors that regulate multicellular responses, such as macrophage migration, neutrophil invasion and chemotaxis, have similar structures, classified as α +β. One biological paradox is that many cytokines that vary greatly in function have a similar structure and share receptors. However, homologous cytokines may differ considerably in their mode of interaction with a shared receptor. A few structures for the extracellular regions of cytokine receptors are known, in several cases complexed with their biological target. These structures, coupled with structural alignment of families, indicate areas that control binding to receptors, as opposed to specific areas responsible for the specific activities of this diverse group of proteins. Methods to use cytokine structure to derive better therapeutics are summarized.