CryoEM Seminar @ITQB NOVA - Aušra Domanska
IMpaCT project is happy to announce our 5th Cryo-EM seminar with our expert guest, Aušra Domanska.
Due to the current limitations caused by the COVID-19 pandemic, the seminar will be held in a hybrid manner - limited seats will be available at the ITQB NOVA auditorium and seminar will be live-streamed via a zoom session.
@ ITQB NOVA auditorium & Webinar link
Meeting ID: 825 3454 9659
Passcode: 257370
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Characterization of inhibitor-binding pocket in enteroviruses and its role in genome release
Aušra Domanska
Institute of Biotechnology
University of Helsinki (FI)
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.
Relevant publications:
Rana Abdelnabi, James A. Geraets, Yipeng Ma, Carmen Mirabelli, Justin W. Flatt, Aušra Domanska, Leen Delang, Dirk Jochmans, Timiri Ajay Kumar, Venkatesan Jayaprakash, Barij Nayan Sinha, Pieter Leyssen, Sarah J. Butcher, Johan Neyts. 2019. A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses. PLoS Biol 17(6): e3000281. https://doi.org/10.1371/journal.pbio.3000281.
Justin W. Flatt, Aušra Domanska, Alma L. Seppälä, Sarah J. Butcher. 2021. Identification of a conserved virion-stabilizing network inside the interprotomer pocket of enteroviruses. Commun Biol 4, 250. https://doi.org/10.1038/s42003-021-01779-x.
Visa Ruokolainen*, Aušra Domanska*, Mira Laajala, Maria Pelliccia, Sarah J Butcher, Varpu Marjomäki. 2019.Extracellular albumin and endosomal ions prime enterovirus particles for uncoating that can be prevented by fatty acid saturation. J.Virol. doi: 10.1128/JVI.00599-19