Embracing proteins: structural themes in aptamer–protein complexes

•Traditional aptamers fold into structures with established nucleic acid motifs.•Modified nucleotides expand the repertoire of known nucleic acid structural motifs.•Hydrophobic modifications make essential inter-molecular and intramolecular interactions.•The flexible phosphodiester bond of aptamers allows for high shape complementarity.•In most cases, aptamer binding occurs without a conformational change of the target. Understanding the structural rules that govern specific, high-affinity binding characteristic of aptamer–protein interactions is important in view of the increasing use of aptamers across many applications. From the modest number of 16 aptamer–protein structures currently available, trends are emerging. The flexible phosphodiester backbone allows folding into precise three-dimensional structures using known nucleic acid motifs as scaffolds that orient specific functional groups for target recognition. Still, completely novel motifs essential for structure and function are found in modified aptamers with diversity-enhancing side chains. Aptamers and antibodies, two classes of macromolecules used as affinity reagents with entirely different backbones and composition, recognize protein epitopes of similar size and with comparably high shape complementarity.