Conformational Landscape of Cytochrome P450 Reductase Interactions

Int J Mol Sci. 2021 Jan 20;22(3):1023. doi: 10.3390/ijms22031023.


Oxidative reactions catalyzed by Cytochrome P450 enzymes (CYPs), which constitute the most relevant group of drug-metabolizing enzymes, are enabled by their redox partner Cytochrome P450 reductase (CPR). Both proteins are anchored to the membrane of the endoplasmic reticulum and the CPR undergoes a conformational change in order to interact with the respective CYP and transfer electrons. Here, we conducted over 22 microseconds of molecular dynamics (MD) simulations in combination with protein-protein docking to investigate the conformational changes necessary for the formation of the CPR-CYP complex. While some structural features of the CPR and the CPR-CYP2D6 complex that we highlighted confirmed previous observations, our simulations revealed additional mechanisms for the conformational transition of the CPR. Unbiased simulations exposed a movement of the whole protein relative to the  membrane, potentially to facilitate interactions with its diverse set of redox partners. Further, we present a structural mechanism for the susceptibility of the CPR to different redox states based on the flip of a glycine residue disrupting the local interaction network that maintains inter-domain proximity. Simulations of the CPR-CYP2D6 complex pointed toward an additional interaction surface of the FAD domain and the proximal side of CYP2D6. Altogether, this study provides novel structural insight into the mechanism of CPR-CYP interactions and underlying conformational changes, improving our understanding of this complex machinery Cytochrome P450 reductase; CPR; conformational; dynamicsrelevant for drug metabolism.

Keywords: CPR; Cytochrome P450 reductase; conformational; dynamics.

MeSH terms

  • Binding Sites
  • Cytochrome P-450 CYP2D6 / chemistry
  • Cytochrome P-450 CYP2D6 / metabolism
  • Flavin-Adenine Dinucleotide / chemistry
  • Flavin-Adenine Dinucleotide / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • NADPH-Ferrihemoprotein Reductase / chemistry*
  • NADPH-Ferrihemoprotein Reductase / metabolism
  • Protein Binding
  • Protein Multimerization


  • Flavin-Adenine Dinucleotide
  • Cytochrome P-450 CYP2D6
  • NADPH-Ferrihemoprotein Reductase