Unraveling the Mechanism of Action of Myricetin in the Inhibition of hUba1 Ubiquitin Thioester Bond Formation via in silico Molecular Modeling Techniques

Gaur, Paras and Tyagi, Chetna (2023) Unraveling the Mechanism of Action of Myricetin in the Inhibition of hUba1 Ubiquitin Thioester Bond Formation via in silico Molecular Modeling Techniques. ACS OMEGA, 8 (33). pp. 30432-30441. ISSN 2470-1343

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Abstract

Ubiquitination is a crucial type of protein modificationwhichhelps to control substrate degradation and maintain cell homeostasis.Recent studies suggest that ubiquitination and deubiquitination areinvolved in regulating metabolic reprogramming in cancer cells andmaintaining cancer stem cells. Uba1, a crucial protein in the ubiquitinationcascade, can be targeted to develop effective inhibitors for cancertreatment. In previous work, we showed that myricetin (Myr) acts asa potential human Uba1 (hUba1) inhibitor. In this study, we have utilizedcomputational modeling techniques to attempt to illustrate the mechanismof action of Myr. Through extra-precision docking, we confirmed thatMyr binds to the adenosine triphosphate (ATP)-binding site of hUba1(referred to as hotspot 1) with the highest binding affinity. Thedynamics of this interaction revealed that hUba1 undergoes a conformationalshift from open to closed upon binding of Myr. Myr also migrates outwardto interact with the crossover loop simultaneously as the rotationalshift of the ubiquitin fold domain (UFD) takes place, thereby blockingaccess to the ubiquitin binding interface of hUba1 and the crossoverloop. The outward migration also explains the reversible nature ofMyr binding to hUba1 in previous experiments. We hypothesize thatMyr acts as an inhibitor of Uba1 & SIM;Ub thioester bond formationby causing a large domain shift toward a closed conformation. Fewother analogues of Myr containing the same flavone skeleton showedpromising docking scores against hUba1 and could be considered forfurther validation. We propose that Myr and some of its analoguesreported in this study may be promising candidates for developingeffective Uba1 inhibitors for cancer treatment.

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