Dengue virus protease activity modulated by dynamics of protease cofactor

The viral protease domain (NS3pro) of dengue virus is essential for virus replication, and its cofactor NS2B is indispensable for the proteolytic function. Although several NS3pro-NS2B complex structures have been obtained, the dynamic property of the complex remains poorly understood. Using NMR relaxation techniques, here we found that NS3pro-NS2B exists in both closed and open conformations that are in dynamic equilibrium on a submillisecond timescale in aqueous solution. Our structural information indicates that the C-terminal region of NS2B is disordered in the minor open conformation but folded in the major closed conformation. Using mutagenesis, we showed that the closed-open conformational equilibrium can be shifted by changing NS2B stability. Moreover, we revealed that the proteolytic activity of NS3pro-NS2B correlates well with the population of the closed conformation. Our results suggest that the closed-open conformational equilibrium can be used by both nature and humanity to control the replication of dengue virus.

Automated summary

The study revealed the dynamic equilibrium between closed and open conformations of the NS3 protease-NS2B complex of dengue virus in aqueous solution. The stability of NS2B was found to affect the equilibrium between closed and open conformations, with the proteolytic activity of the complex correlating well with the closed conformation. These findings suggest that the closed-open conformational equilibrium can be utilized to control the replication of dengue virus by both nature and human intervention.