Conformational Dynamics in the Interaction of SARS-CoV-2 Papain-like Protease with Human Interferon-Stimulated Gene 15 Protein.
Wellington C LeiteKevin L WeissGwyndalyn PhillipsQiu ZhangShuo QianSusan E TsutakawaLeighton CoatesHugh Michael O'NeillPublished in: The journal of physical chemistry letters (2021)
Papain-like protease (PLpro) from SARS-CoV-2 plays essential roles in the replication cycle of the virus. In particular, it preferentially interacts with and cleaves human interferon-stimulated gene 15 (hISG15) to suppress the innate immune response of the host. We used small-angle X-ray and neutron scattering combined with computational techniques to study the mechanism of interaction of SARS-CoV-2 PLpro with hISG15. We showed that hISG15 undergoes a transition from an extended to a compact state after binding to PLpro, a conformation that has not been previously observed in complexes of SARS-CoV-2 PLpro with ISG15 from other species. Furthermore, computational analysis showed significant conformational flexibility in the ISG15 N-terminal domain, suggesting that it is weakly bound to PLpro and supports a binding mechanism that is dominated by the C-terminal ISG15 domain. This study fundamentally improves our understanding of the SARS-CoV-2 deISGylation complex that will help guide development of COVID-19 therapeutics targeting this complex.
Keyphrases
- sars cov
- immune response
- respiratory syndrome coronavirus
- endothelial cells
- dendritic cells
- molecular dynamics simulations
- high resolution
- molecular dynamics
- genome wide
- coronavirus disease
- copy number
- magnetic resonance imaging
- binding protein
- dna methylation
- pluripotent stem cells
- gene expression
- small molecule
- computed tomography
- magnetic resonance
- cancer therapy
- mass spectrometry
- genetic diversity
- amino acid
- dual energy