Evolution of Protein Wrapping and Implications for the Drug Designer

Abstract

Proteins with common ancestry (homologs) typically share a common fold. This structural similarity introduces major problems for rational drug design since a major goal in the field is the control of specificity. Yet, as shown in this chapter, while the topology of the native structure is extremely similar across homologs, their wrapping patterns and expression regulation tend to be different, offering a novel opportunity to funnel the impact of a drug on clinically relevant targets. The evolutionary root of these dissimilarities across homologous proteins is carefully dissected in this chapter both across species and within the human species. Furthermore, as hinted in this and demonstrated in subsequent chapters, the wrapping variations across homologs have profound consequences for drug design as we aim at engineering target-specific and species-specific therapeutic agents and build insightful animal models for disease or malignancy.