Human rhinoviruses (HRVs) are the predominant infectious agents for the common cold worldwide. The HRV-C species cause severe illnesses in children and are closely related to acute exacerbations of asthma. 3C protease, a highly conserved enzyme, cleaves the viral polyprotein during replication and assists the virus in escaping the host immune system. These key roles make 3C protease an important drug target. A few structures of 3Cs complexed with an irreversible inhibitor rupintrivir have been determined. These structures shed light on the determinants of drug specificity. Here we describe the structures of HRV-C15 3C in free and inhibitor-bound forms. The volume-decreased S1' subsite and half-closed S2 subsite, which were thought to be unique features of enterovirus A 3C proteases, appear in the HRV-C 3C protease. Rupintrivir assumes an "intermediate" conformation in the complex, which might open up additional avenues for the design of potent antiviral inhibitors. Analysis of the features of the three-dimensional structures and the amino acid sequences of 3C proteases suggest new applications for existing drugs.
Keyphrases
- high resolution
- drug induced
- chronic obstructive pulmonary disease
- amino acid
- endothelial cells
- young adults
- transcription factor
- sars cov
- cystic fibrosis
- minimally invasive
- intensive care unit
- mass spectrometry
- induced pluripotent stem cells
- respiratory failure
- early onset
- adverse drug
- molecular dynamics simulations
- genetic diversity
- anti inflammatory
- acute respiratory distress syndrome
- extracorporeal membrane oxygenation
- structural basis
- mechanical ventilation