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

DOI: 10.1016/j.virol.2021.07.008 DOI Help

Authors: Karin M. Deutschmann-Olek (Medical University of Vienna) , Wyatt W. Yue (University of Oxford) , Gustavo A. Bezerra (University of Oxford) , Tim Skern (Medical University of Vienna)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Virology , VOL 562 , PAGES 128 - 141

State: Published (Approved)
Published: October 2021
Diamond Proposal Number(s): 20221

Open Access Open Access

Abstract: 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.

Journal Keywords: Rhinovirus; Virus-host interaction; Cysteine proteinase; Fluoromethylketone inhibitor; Translation initiation; Anti-viral agent

Diamond Keywords: Rhinoviruses; Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
1-s2.0-S0042682221001550-main.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)