The effect of dimerization and ligand binding on the dynamics of Kaposi's sarcoma‐associated herpesvirus protease

Abstract

The Kaposi's sarcoma-associated herpesvirus protease is essential for virus maturation. This protease functions under allosteric regulation that establishes its enzymatic activity upon dimerization. It exists in equilibrium between an inactive monomeric state and an active, weakly associating, dimeric state that is stabilized upon ligand binding. The dynamics of the protease dimer and its monomer were studied using the Gaussian network model and the anisotropic network model , and its role in mediating the allosteric regulation is demonstrated. We show that the dimer is composed of five dynamical domains. The central domain is formed upon dimerization and composed of helix five of each monomer, in addition to proximal and distal domains of each monomer. Dimerization reduces the mobility of the central domains and increases the mobility of the distal domains, in particular the binding site within them. The three slowest ANM modes of the dimer assist the protease in ligand binding, motion of the conserved Arg142 and Arg143 toward the oxyanion, and reducing the activation barrier for the tetrahedral transition state by stretching the bond that is cleaved by the protease. In addition, we show that ligand binding reduces the motion of helices α1 and α5 at the interface and explain how ligand binding can stabilize the dimer.

An Assessment of Quaternary Structure Functionality in Homomer Protein Complexes

“…To test whether interfaces are necessary for performing the biochemical function of the proteins, we next examined whether interfaces coevolve with ligand-binding residues (LBRs). Multimerization may modulate function in several ways; for example, binding sites may be active only in complex ( Bern and Tobi 2022 ), interfaces may influence their specificity ( Rausell et al 2010 ), or the ligands may communicate allosterically across the interface ( Stefan and Le Novère 2013 ). We expected that in many complexes where multimerization does contribute to function, LBRs coevolve more strongly with interface residues than with the solvent-accessible residues of the surface.…”

Genomic characterization of Rocahepevirus ratti hepatitis E virus genotype C1 in Yunnan province of China

“…Furthermore, the majority of substitutions in HEV-C1 genomes were close to the predicted ligand binding sites, differing from L 238 F in MSE-17 and T 234 V in OP610066. Ligand binding and structural change in the ligand region can affect viral dynamics ( Bern and Tobi, 2022 ). However, it remains unclear if and how the localization of substitutions influences the infection of HEV-C1, which warrants further studies on the mechanisms of HEV-C1 infection in animals and humans.…”