Evolutionary studies of ligand binding sites in proteins

•Promiscuity is an important driver of the divergent functional evolution of ligand binding-sites.•Enzymatic functions across protein families are related.•Evolutionarily unrelated proteins may bind the same ligand using the same or distinct functional groups.•Small differences in ligand binding-sites may have drastic effects.•Binding-site evolution affects both the specificity and selectivity of interactions within the cellular context.

Biological processes at their most fundamental molecular aspects are defined by molecular interactions with ligand-protein interactions in particular at the core of cellular functions such as metabolism and signalling. Divergent and convergent processes shape the evolution of ligand binding sites. The competition between similar ligands and binding sites across protein families create evolutionary pressures that affect the specificity and selectivity of interactions. This short review showcases recent studies of the evolution of ligand binding-sites and methods used to detect binding-site similarities.

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