Conserved structural motifs in PAS, LOV, and CRY proteins regulate circadian rhythms and are therapeutic targets.

Despite evolving independently in diverse organisms, circadian clocks ubiquitously employ period-ARNT-single minded (PAS) and cryptochrome (CRY) proteins as key regulators coupling environmental variables into circadian regulation. In these systems, we often observe complex gene duplication events and evolution of specialized function despite retaining high-sequence identity. These specialized functions often have evolved from ancestral photoactive proteins (LOV/CRY) where upon the ancestral photoactive ligand-binding pockets have been co-opted as protein-protein interaction motifs and targets for drug discovery. In this review, we dissect structural, biochemical, and computational studies of the PAS and CRY superfamilies within circadian clocks to highlight their molecular mechanisms and factors that position them as drug targets for diverse disease phenotypes. Particular focus is placed on discussing how photoactive members of the protein families can inform on allosteric mechanisms that couple cofactor-binding sites to regulation of flexible signaling motifs relevant to circadian regulation and drug discovery.