ArticlePloS one2015
NMR and MD Studies Reveal That the Isolated Dengue NS3 Protease Is an Intrinsically Disordered Chymotrypsin Fold Which Absolutely Requests NS2B for Correct Folding and Functional Dynamics.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 49 citations in OpenAlex.
- Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development.Viruses · 2026Review
- Achievements and Approaches in the Search for Small-Molecule Dengue NS2B/NS3 Inhibitors.Current medicinal chemistry · 2026Review
- Exploring the viral protease inhibitor space driven by consensus scoring-based virtual screening.In silico pharmacology · 2024Article
- Duck Tembusu virus NS3 protein induces apoptosis by activating the PERK/PKR pathway and mitochondrial pathway.Journal of virology · 2023Article
- Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro.Communications biology · 2023Article
- Structural Modifications Introduced by NS2B Cofactor Binding to the NS3 Protease of the Kyasanur Forest Disease Virus.International journal of molecular sciences · 2023Article
- A competition smFRET assay to study ligand-induced conformational changes of the dengue virus protease.Protein science : a publication of the Protein Society · 2023Article
- The cargo adapter protein CLINT1 is phosphorylated by the Numb-associated kinase BIKE and mediates dengue virus infection.The Journal of biological chemistry · 2022Article
- Myricetin Allosterically Inhibits the Dengue NS2B-NS3 Protease by Disrupting the Active and Locking the Inactive Conformations.ACS omega · 2022Article
- Precursors of Viral Proteases as Distinct Drug Targets.Viruses · 2021Review
- Article
- Curcumin Allosterically Inhibits the Dengue NS2B-NS3 Protease by Disrupting Its Active Conformation.ACS omega · 2020Article
- Discovery of Zika Virus NS2B/NS3 Inhibitors That Prevent Mice from Life-Threatening Infection and Brain Damage.ACS medicinal chemistry letters · 2020Article
- Insights into Structures and Dynamics of Flavivirus Proteases from NMR Studies.International journal of molecular sciences · 2020Review
- Structurally- and dynamically-driven allostery of the chymotrypsin-like proteases of SARS, Dengue and Zika viruses.Progress in biophysics and molecular biology · 2019Review
- Strategies Towards Protease Inhibitors for Emerging Flaviviruses.Advances in experimental medicine and biology · 2018Review
- TMEM106B, a risk factor for FTLD and aging, has an intrinsically disordered cytoplasmic domain.PloS one · 2018Article
- Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond.Nature reviews. Drug discovery · 2017Review
- Host-Virus Interaction of ZIKA Virus in Modulating Disease Pathogenesis.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2017Review
- Structural features of NS3 of Dengue virus serotypes 2 and 4 in solution and insight into RNA binding and the inhibitory role of quercetin.Acta crystallographica. Section D, Structural biology · 2017Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dengue genome encodes a two component protease complex (NS2B-NS3pro) essential for the viral maturation/infectivity, thus representing a key drug target. Previously, due to its "complete insolubility", the isolated NS3pro could not be experimentally studied and it remains elusive what structure it adopts without NS2B and why NS2B is indispensable. Here as facilitated by our previous discovery, the isolated NS3pro has been surprisingly deciphered by NMR to be the first intrinsically-disordered chymotrypsin-like fold, which exists in a loosely-packed state with non-native long-range interactions as revealed by paramagnetic relaxation enhancement (PRE). The disordered NS3pro appears to be needed for binding a human host factor to trigger the membrane remodeling. Moreover, we have in vitro refolded the NS3pro in complex with either NS2B (48-100) or the full-length NS2B (1-130) anchored into the LMPC micelle, and the two complexes have similar activities but different dynamics. We also performed molecular dynamics (MD) simulations and the results revealed that NS2B shows the highest structural fluctuations in the complex, thus providing the dynamic basis for the observation on its conformational exchange between open and closed states. Remarkably, the NS2B cofactor plays a central role in maintaining the correlated motion network required for the catalysis as we previously decoded for the SARS 3CL protease. Indeed, a truncated NS2B (48-100;Δ77-84) with the flexible loop deleted is able to trap the NS2B-NS3pro complex in a highly dynamic and catalytically-impotent state. Taken together, our study implies potential strategies to perturb the NS2B-NS3pro interface for design of inhibitors for treating dengue infection.
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