Julie V. Nguyen
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Research Subjects
Julie V. Nguyen has a total of 13 co-authors. Here are the top co-authors by number of shared publications:
- Bernadine G. C. Lu
The Walter and Eliza Hall Institute for Medical Research, Parkville, Australia
2 shared publications - Dale J. Calleja
The Walter and Eliza Hall Institute for Medical Research, Parkville, Australia
2 shared publications - David Komander
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
2 shared publications - Guillaume Lessene
Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
2 shared publications - Jeffrey P. Mitchell
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
2 shared publications - Kym N. Lowes
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2 shared publications
Latest Publications
- Open Access
- 23 July 2024
- Published by Springer Nature in Nature Communications
- Vol. 15 (1) , 1-18
Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape
Papain-like protease (PLpro) is an attractive drug target for SARS-CoV-2 because it is essential for viral replication, cleaving viral poly-proteins pp1a and pp1ab, and has de-ubiquitylation and de-ISGylation activities, affecting innate immune responses. We employ Deep Mutational Scanning to evaluate the mutational effects on PLpro enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify mutations in neighboring residues that alter activity. We characterize residues responsible for substrate binding and demonstrate that although residues in the blocking loop are remarkably tolerant to mutation, blocking loop flexibility is important for function. We additionally find a connected network of mutations affecting activity that extends far from the active site. We leverage our library to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.
- 23 July 2024
- Published by Springer Nature in Nature Communications
- Vol. 15 (1) , 1-18
Open AccessMutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape
Papain-like protease (PLpro) is an attractive drug target for SARS-CoV-2 because it is essential for viral replication, cleaving viral poly-proteins pp1a and pp1ab, and has de-ubiquitylation and de-ISGylation activities, affecting innate immune responses. We employ Deep Mutational Scanning to evaluate the mutational effects on PLpro enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify mutations in neighboring residues that alter activity. We characterize residues responsible for substrate binding and demonstrate that although residues in the blocking loop are remarkably tolerant to mutation, blocking loop flexibility is important for function. We additionally find a connected network of mutations affecting activity that extends far from the active site. We leverage our library to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.
- Open Access
Mutational Profiling of SARS-CoV-2 PLpro in human cells reveals requirements for function, structure, and drug escape
SARS-CoV-2, the causative agent of COVID-19, is responsible for the recent global pandemic and remains a major source of mortality. Papain-like protease (PLpro) is a target for SARS-CoV-2 inhibitor development, as it is not only essential for viral replication through cleavage of the viral poly-proteins pp1a and pp1ab, but also has de-ubiquitylation and de-ISGylation activities, which can affect innate immune responses. To understand the features of PLpro that dictate activity and anticipate how emerging PLpro variants will affect function, we employed Deep Mutational Scanning to evaluate the mutational effects on enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify all mutations in neighboring residues that support or ablate activity. We characterize residues responsible for substrate binding and demonstrate that although the blocking loop is remarkably tolerant to nearly all mutations, its flexibility is important for enzymatic function. We additionally find a connected network of mutations affecting function but not structure that extends far from the active site. Using our DMS libraries we were able to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.
Open AccessMutational Profiling of SARS-CoV-2 PLpro in human cells reveals requirements for function, structure, and drug escape
SARS-CoV-2, the causative agent of COVID-19, is responsible for the recent global pandemic and remains a major source of mortality. Papain-like protease (PLpro) is a target for SARS-CoV-2 inhibitor development, as it is not only essential for viral replication through cleavage of the viral poly-proteins pp1a and pp1ab, but also has de-ubiquitylation and de-ISGylation activities, which can affect innate immune responses. To understand the features of PLpro that dictate activity and anticipate how emerging PLpro variants will affect function, we employed Deep Mutational Scanning to evaluate the mutational effects on enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify all mutations in neighboring residues that support or ablate activity. We characterize residues responsible for substrate binding and demonstrate that although the blocking loop is remarkably tolerant to nearly all mutations, its flexibility is important for enzymatic function. We additionally find a connected network of mutations affecting function but not structure that extends far from the active site. Using our DMS libraries we were able to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.