Revealing and utilizing receptor recognition mechanisms in a high-throughput world

Recent genomic mapping promises to identify essentially all of the proteins that underpin normal and aberrant biology in humans. What genomics leaves undone is to determine how these proteins interact and integrate into molecular pathways in health and disease. Specific molecular interactions provide the fundamental mechanism for selectivity in virtually every aspect of biological structure and function. The convergence of structural and mutational studies makes it possible to define what parts of a protein are important for recognition. Still, knowing what is important does not necessarily foretell how binding epitopes actually function. We have applied the approach of epitope randomization on phage to explore how structural elements in such receptor recruitment systems as interleukin-5 (IL-5) and HIV-1 function in receptor recognition. This work has led in the IL-5 case to differentiation of recognition and activation epitopes, and this in turn has potential to help in the design of non-activating mimetics that could stimulate development of therapeutic antagonists for allergic inflammations such as asthma. Whether it is possible to differentiate recognition and activation in designing inhibitors in cases such as HIV-1 cell attachment and infection remains a tantalizing, but unsolved goal at present. Overall, these studies portray advances as well as limitations in the effort to decipher protein recognition mechanisms and utilize the wisdom gained for mechanism-based antagonist design in an increasingly high throughput world stimulated by the advent of genomics and proteomics.