Next Article in Journal
The Effect of Transmembrane Protein Shape on Surrounding Lipid Domain Formation by Wetting
Previous Article in Journal
Anti-Atherosclerotic Effects of Fruits of Vitex rotundifolia and Their Isolated Compounds via Inhibition of Human LDL and HDL Oxidation
Open AccessArticle

A Dynamic Core in Human NQO1 Controls the Functional and Stability Effects of Ligand Binding and Their Communication across the Enzyme Dimer

1
Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic
2
Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43 Prague 2, Czech Republic
3
Center for Rare Diseases (CIBERER), Hospital Universitario de Canarias, Universidad de La Laguna, 38320 Tenerife, Spain
4
School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton BN2 4GJ, UK
5
Department of Physical Chemistry and Unit of Excellence in Chemistry, University of Granada, Av. Fuentenueva s/n, E-18071 Granada, Spain
*
Authors to whom correspondence should be addressed.
Biomolecules 2019, 9(11), 728; https://doi.org/10.3390/biom9110728
Received: 23 October 2019 / Revised: 6 November 2019 / Accepted: 10 November 2019 / Published: 12 November 2019
(This article belongs to the Section Molecular Structure and Dynamics)
Human NAD(P)H:quinone oxidoreductase 1 (NQO1) is a multi-functional protein whose alteration is associated with cancer, Parkinson’s and Alzheimer´s diseases. NQO1 displays a remarkable functional chemistry, capable of binding different functional ligands that modulate its activity, stability and interaction with proteins and nucleic acids. Our understanding of this functional chemistry is limited by the difficulty of obtaining structural and dynamic information on many of these states. Herein, we have used hydrogen/deuterium exchange monitored by mass spectrometry (HDXMS) to investigate the structural dynamics of NQO1 in three ligation states: without ligands (NQO1apo), with FAD (NQO1holo) and with FAD and the inhibitor dicoumarol (NQO1dic). We show that NQO1apo has a minimally stable folded core holding the protein dimer, with FAD and dicoumarol binding sites populating binding non-competent conformations. Binding of FAD significantly decreases protein dynamics and stabilizes the FAD and dicoumarol binding sites as well as the monomer:monomer interface. Dicoumarol binding further stabilizes all three functional sites, a result not previously anticipated by available crystallographic models. Our work provides an experimental perspective into the communication of stability effects through the NQO1 dimer, which is valuable for understanding at the molecular level the effects of disease-associated variants, post-translational modifications and ligand binding cooperativity in NQO1. View Full-Text
Keywords: protein structural dynamics; NQO1; ligand binding; protein stability; allostery; protein degradation protein structural dynamics; NQO1; ligand binding; protein stability; allostery; protein degradation
Show Figures

Figure 1

MDPI and ACS Style

Vankova, P.; Salido, E.; Timson, D.J.; Man, P.; Pey, A.L. A Dynamic Core in Human NQO1 Controls the Functional and Stability Effects of Ligand Binding and Their Communication across the Enzyme Dimer. Biomolecules 2019, 9, 728.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop