ArticleScientific reports2016
Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 23 papers.
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23 citing papers in PubMed, 49 citations in OpenAlex.
- Tyrosine residues at the substrate binding site in human NQO1 homodimer: Protein conformational dynamics and optimization of substrate binding geometry.The FEBS journal · 2026Article
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- Allosteric Communication in the Multifunctional and Redox NQO1 Protein Studied by Cavity-Making Mutations.Antioxidants (Basel, Switzerland) · 2022Article
- Targeting HIF-1α Function in Cancer through the Chaperone Action of NQO1: Implications of Genetic Diversity of NQO1.Journal of personalized medicine · 2022Review
- Probing altered enzyme activity in the biochemical characterization of cancer.Bioscience reports · 2022Review
- Redox state and the sirtuin deacetylases are major factors that regulate the acetylation status of the stress protein NQO1.Frontiers in pharmacology · 2022Article
- Article
- The diverse functionality of NQO1 and its roles in redox control.Redox biology · 2021Review
- Galactosemia: Towards Pharmacological Chaperones.Journal of personalized medicine · 2021Review
- An aspartyl protease-mediated cleavage regulates structure and function of a flavodoxin-like protein and aids oxidative stress survival.PLoS pathogens · 2021Article
- Ferroptosis-Related Flavoproteins: Their Function and Stability.International journal of molecular sciences · 2021Review
- Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein.Journal of personalized medicine · 2020Article
- The Catalytic Cycle of the Antioxidant and Cancer-Associated Human NQO1 Enzyme: Hydride Transfer, Conformational Dynamics and Functional Cooperativity.Antioxidants (Basel, Switzerland) · 2020Article
- A small molecule chaperone rescues the stability and activity of a cancer-associated variant of NAD(P)H:quinone oxidoreductase 1 in vitro.FEBS letters · 2020Article
- A Dynamic Core in Human NQO1 Controls the Functional and Stability Effects of Ligand Binding and Their Communication across the Enzyme Dimer.Biomolecules · 2019Article
- Cancer-associated variants of human NQO1: impacts on inhibitor binding and cooperativity.Bioscience reports · 2019Article
- NAD(P)H quinone oxidoreductase (NQO1): an enzyme which needs just enough mobility, in just the right places.Bioscience reports · 2019Review
- A Hotspot for Disease-Associated Variants of Human PGM1 Is Associated with Impaired Ligand Binding and Loop Dynamics.Structure (London, England : 1993) · 2018Article
- Review
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein dynamics is essential to understand protein function and stability, even though is rarely investigated as the origin of loss-of-function due to genetic variations. Here, we use biochemical, biophysical, cell and computational biology tools to study two loss-of-function and cancer-associated polymorphisms (p.R139W and p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs and stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes the NQO1 dimer in vitro and increases the flexibility of the C-terminal domain, while a combination of FAD and the inhibitor dicoumarol overcome these alterations. Additionally, changes in global stability due to polymorphisms and ligand binding are linked to the dynamics of the dimer interface, whereas the low activity and affinity for FAD in p.P187S is caused by increased fluctuations at the FAD binding site. Importantly, NQO1 steady-state protein levels in cell cultures correlate primarily with the dynamics of the C-terminal domain, supporting a directional preference in NQO1 proteasomal degradation and the use of ligands binding to this domain to stabilize p.P187S in vivo. In conclusion, protein dynamics are fundamental to understanding loss-of-function in p.P187S, and to develop new pharmacological therapies to rescue this function.
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