In a study published in Nature Communications, an international group of researchers from Switzerland, France, Uruguay, Brazil, USA, and Germany uncovered how the histidine kinase LvrB from pathogenic Leptospira is activated. LvrB is a central component of the Lvr signaling system, which controls virulence in these bacteria, and belongs to the broadly distributed family of two-component signaling enzymes. Despite their importance, the molecular basis of activation in this class of proteins has remained poorly understood.
By combining cryo-EM structural analysis with all-atom molecular dynamics simulations, the study provides detailed insight into how LvrB switches from an inactive to an active state. Cryo-EM structures obtained at the Biozentrum of the University of Basel in the group of Prof. Sebastian Hiller show that inactive LvrB adopts a symmetric arrangement in which the catalytic domains are tightly restrained. Upon phosphorylation, this symmetry is broken, releasing the catalytic domains into a more dynamic and active configuration.
A key contribution to the mechanistic understanding came from Kristyna Pluhackova, whose molecular dynamics simulations provided a dynamic view of two central steps in the activation process. The simulations showed how Rec phosphorylation reshapes a previously unrecognized variation of the canonical Y–T switch, an “inverse Y–T switch”, characterized by coordinated anticorrelated movements of key tyrosine residues. They further revealed how coiled-coil formation of the central helices connecting the Rec and DHp domains induces bending of the helical core and thereby drives asymmetric activation. In silico experiments additionally demonstrated that this behavior can be disrupted by shortening the central helices or by a targeted mutation, highlighting the structural determinants of the switch.
The work establishes a mechanistic framework for Rec-controlled histidine kinases and demonstrates how molecular simulations can uncover the dynamic basis of bacterial signaling and pathogenicity when integrated with structural and functional experiments.