In this review, we discuss recent advances in circadian research and the potential for therapeutic applications that take patient circadian rhythms into account in treating disease. With growing knowledge of the molecular and cellular mechanisms underlying circadian physiology and pathophysiology, it is becoming possible to target circadian rhythms for disease prevention and treatment. virus and parasite infections), and medical interventions (e.g. Studies with animal and human models have also unraveled an important role of functional circadian clocks in modulating cellular and organismal responses to physiological cues (ex., food intake, exercise), pathological insults (e.g. The adaptive value of clocks is evident when internal body clocks and daily environmental cycles are mismatched, such as in the case of shift work and jet lag or even mistimed eating, all of which are associated with physiological disruption and disease. These two hydrogen bonds together with a network of hydrophobic and stacking interactions with V66, H160, and M163 support the high potency and selectivity of the compound for CK2.Ĭircadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and metabolism. Hydroxyl and methoxy groups form hydrogen bonds to K68. The bromoguaiacol group of GO289 binds indirectly via a water molecule (W2) to the hinge backbone carbonyl of E114 and V116 amide in a noncanonical interaction. (B) CK2a in complex with GO289 (cyan) (PDB: 6A1C). The carboxylate group of the compound forms a hydrogen bond with K68, and is stabilized by the coordination of two water molecules (W1 and W2). The pyridine nitrogen in CX-4945 makes a canonical hydrogen bond to the backbone of V116 in the hinge.
(A) CK2a in complex with CX-4945 (light pink) (PDB: 3PE1).
Water molecules are shown as red spheres. Hydrogen bonds, halogen bonds, and cation-p interactions are indicated by red, yellow, and blue dashed lines, respectively. Nitrogen, oxygen, sulfur, chlorine, and bromine atoms are colored blue, red, gold, green, and brown, respectively. Compound-interacting residues of CK2a are shown as sticks. CK2a structures are shown as white cartoons with the hinge region colored dark gray. Crystal structures of CK2a in complex with small-molecule inhibitors bound to the ATP-binding pocket.