Abstract
Per-Arnt-Sim (PAS) domain kinase (PASK) is a conserved metabolic sensor that modulates the activation of critical proteins involved in liver metabolism and fitness. However, despite its key role in mastering the metabolic regulation, the molecular mechanism of PASK's activity is ongoing research, and structural information of this important protein is scarce. To investigate this, we integrated structural bioinformatics with state-of-the-art modeling and molecular simulation techniques. Our goals were to address (1) how many regulatory PAS domains PASK is likely to have, (2) how those domains modulate the kinase activity, and (3) how those interactions could be controlled by small molecules. Our results indicated the existence of three N-terminal PAS domains. Solvent mapping and fragment docking identified a consensus set of 'druggable hot spots' within all domains, as well as at domain-domain interfaces. Those 'hot spots' could be modulated with chemically diverse small molecular probes, which may serve as a starting point for rationally designed therapeutics modulating these specific sites. Our results identified a plausible mechanism of autoinhibition of kinase activity, suggesting that all three putative PAS domains may be required. Future work will focus on validation of the predicted PASK models and development of small-molecule inhibitors of PASK by targeting its 'druggable hot spots'.