Properties of Oligomeric Interaction of the Cytomegalovirus Core Nuclear Egress Complex (NEC) and Its Sensitivity to an NEC Inhibitory Small Molecule
Kicuntod J, Alkhashrom S, Häge S, Diewald B, Müller R, Hahn F, Lischka P, Sticht H, Eichler J, Marschall M (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 13
Journal Issue: 3
DOI: 10.3390/v13030462
Abstract
Herpesviral nuclear egress is a regulated process shared by all family members, ensuring the efficient cytoplasmic release of viral capsids. In the case of human cytomegalovirus (HCMV), the core of the nuclear egress complex (NEC) consists of the pUL50-pUL53 heterodimer that builds hexameric lattices for capsid binding and multicomponent interaction, including NEC-associated host factors. A characteristic feature of NEC interaction is the N-terminal hook structure of pUL53 that binds to an alpha-helical groove of pUL50, thus termed as hook-into-groove interaction. This central regulatory element is essential for viral replication and shows structural-functional conservation, which has been postulated as a next-generation target of antiviral strategies. However, a solid validation of this concept has been missing. In the present study, we focused on the properties of oligomeric HCMV core NEC interaction and the antiviral activity of specifically targeted prototype inhibitors. Our data suggest the following: (i) transiently expressed, variably tagged versions of HCMV NEC proteins exert hook-into-groove complexes, putatively in oligomeric assemblies that are distinguishable from heterodimers, as shown by in vitro assembly and coimmunoprecipitation approaches; (ii) this postulated oligomeric binding pattern was further supported by the use of a pUL50::pUL53 fusion construct also showing a pronounced multi-interaction potency; (iii) using confocal imaging cellular NEC-associated proteins were found partly colocalized with the tagged core NECs; (iv) a small inhibitory molecule, recently identified by an in vitro binding inhibition assay, was likewise active in blocking pUL50-pUL53 oligomeric assembly and in exerting antiviral activity in HCMV-infected fibroblasts. In summary, the findings refine the previous concept of HCMV core NEC formation and nominate this drug-accessible complex as a validated antiviral drug target.
Authors with CRIS profile
Jintawee Kicuntod
Professur für Pharmazeutische Chemie
Sewar Alkhashrom
Lehrstuhl für Pharmazeutische Chemie
Sigrun Häge
Institute of Clinical and Molecular Virology
Benedikt Diewald
Professur für Bioinformatik
Friedrich Hahn
Professur für Virologie
Heinrich Sticht
Professur für Bioinformatik
Jutta Eichler
Professur für Pharmazeutische Chemie
Manfred Marschall
Lehrstuhl für Klinische und Molekulare Virologie
Involved external institutions
Germany (DE)How to cite
APA:
Kicuntod, J., Alkhashrom, S., Häge, S., Diewald, B., Müller, R., Hahn, F.,... Marschall, M. (2021). Properties of Oligomeric Interaction of the Cytomegalovirus Core Nuclear Egress Complex (NEC) and Its Sensitivity to an NEC Inhibitory Small Molecule. Viruses, 13(3). https://dx.doi.org/10.3390/v13030462
MLA:
Kicuntod, Jintawee, et al. "Properties of Oligomeric Interaction of the Cytomegalovirus Core Nuclear Egress Complex (NEC) and Its Sensitivity to an NEC Inhibitory Small Molecule." Viruses 13.3 (2021).
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