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Defining substrate selection by rhinoviral 2A proteinase through its crystal structure with the inhibitor zVAM.fmk

Lookup NU author(s): Professor Wyatt YueORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2021 The Authors. Picornavirus family members cause disease in humans. Human rhinoviruses (RV), the main causative agents of the common cold, increase the severity of asthma and COPD; hence, effective agents against RVs are required. The 2A proteinase (2Apro), found in all enteroviruses, represents an attractive target; inactivating mutations in poliovirus 2Apro result in an extension of the VP1 protein preventing infectious virion assembly. Variations in sequence and substrate specificity on eIF4G isoforms between RV 2Apro of genetic groups A and B hinder 2Apro as drug targets. Here, we demonstrate that although RV-A2 and RV-B4 2Apro cleave the substrate GAB1 at different sites, the 2Apro from both groups cleave equally efficiently an artificial site containing P1 methionine. We determined the RV-A2 2Apro structure complexed with zVAM.fmk, containing P1 methionine. Analysis of this first 2Apro-inhibitor complex reveals a conserved hydrophobic P4 pocket among enteroviral 2Apro as a potential target for broad-spectrum anti-enteroviral inhibitors.

Publication metadata

Author(s): Deutschmann-Olek KM, Yue WW, Bezerra GA, Skern T

Publication type: Article

Publication status: Published

Journal: Virology

Year: 2021

Volume: 562

Pages: 128-141

Print publication date: 01/10/2021

Online publication date: 21/07/2021

Acceptance date: 16/07/2021

Date deposited: 12/09/2024

ISSN (print): 0042-6822

ISSN (electronic): 1096-0341

Publisher: Academic Press Inc.

URL: https://doi.org/10.1016/j.virol.2021.07.008

DOI: 10.1016/j.virol.2021.07.008

PubMed id: 34315103

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