CryoEM Seminar @ITQB NOVA - Aušra Domanska

Title: Characterization of inhibitor-binding pocket in enteroviruses and it’s role in genome release

Speaker: Aušra Domanska 

Affiliation: Institute of Biotechnology, University of Helsinki (FI)

Abstract: 

Enteroviruses cause a wide variety of illnesses, ranging from the mild common cold to hand-foot-and-mouth disease, myocarditis, pancreatitis, aseptic meningitis, and encephalitis. Their entry can be inhibited by “classical capsid binders,” small molecules targeting a surface-exposed hydrophobic pocket in one of the viral coat proteins (VP1) preventing genome uncoating. However, efficacy, toxicity, emergence of drug-resistant viruses, and existence of enteroviruses lacking the VP1 pocket limit their clinical benefit. Recently, we identified a new druggable site at a conserved interface formed by multiple capsid proteins, the VP1-VP3 interprotomer pocket. We have now determined high-resolution cryo-electron microscopy structures of coxsackieviruses B3 and B4, complexed with the interprotomer-targeting compounds, CP17 and CP48, respectively. At better than 3-Å resolution, we identified the detailed interactions that facilitate ligand binding. Both compounds target the same network with three conserved pocket residues at the core, each originating from a different polypeptide chain, stabilizing the virion. Structural comparison of amino acid residues shows that this pocket is important for enterovirus entry and when inhibitor is bound the viral infection is blocked at an early step. Synergistic development of compounds targeting both pockets, the VP1 and interprotomer pocket, is a promising endeavor in the fight against enteroviruses.

Find out more. 

Join the session in the ITQB NOVA Auditorium or the Zoom Meeting:

https://us02web.zoom.us/j/82534549659?pwd=dEpxTUdoWkl0djVHSmhWM2ZsaUpPZz09