Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands

• DOI: 10.1038/srep20331
• Publication Date: 2016-02-03T10:43:53Z
• Authors: Encarnación Medin...; Rogelio J. Palomi...; Julian E. Fuchs; Esperanza Padín-G...; Noel Mesa-Torres; Eduardo Salido; David J. Timson; Angel L. Pey
• Keywords: Dynamics

Abstract Protein dynamics is essential to understand protein function and stability, even though rarely investigated as the origin of loss-of-function due genetic variations. Here, we use biochemical, biophysical, cell computational biology tools study two cancer-associated polymorphisms (p.R139W p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes NQO1 dimer vitro increases flexibility C-terminal domain, while combination FAD inhibitor dicoumarol overcome these alterations. Additionally, changes global stability ligand binding are linked interface, whereas low activity affinity for caused by increased fluctuations at site. Importantly, steady-state levels cultures correlate primarily with supporting directional preference proteasomal degradation ligands this domain stabilize vivo . In conclusion, fundamental understanding develop new pharmacological therapies rescue function.