Structural Determination of the Conformations of Glutathione Peroxidase‐4 (GPX4) Through Markov State Modeling

Abstract

Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides in lipid membranes, which effectively inhibits iron-dependent cell death, or ferroptosis. This property makes GPX4 an interesting target for drug exploration as the upregulation of the enzyme could help to treat ferroptosis-related neurogenerative diseases (i.e. Alzheimer's, Parkinson's, and Huntington's disease). However, the challenge of upregulating GPX4 is finding an allosteric site and activator that is compatible with the enzyme. GPX4 is globular protein and lacks deep druggable pockets, which makes identifying viable allosteric sites more difficult. Using molecular dynamic (MD) simulations we will computationally map the conformational and energetic landscape of the wild-type protein and along with three mutant variants to identify the allosteric network of the enzyme. The conformational sub-states observed in the MD simulations will then be analyzed to determine any viable allosteric sites on the enzyme in order to activate the enzyme. Support or Funding Information NSF grant number CNS-0619508 Four different variations of GPX4 were simulated using the AMBER molecular dynamic software: Wild Type, Mutation A (D16A), Mutation B (D18A), and Mutation AB (D16A & D18A). The structure of GPX4 was downloaded from the Protein Data Bank (PDB ID: 2OBI). The catalytic triad (pink) is a combination of three amino acid residues: Cys73, Gln108, Trp163. Selenocysteine (Sec73) was modeled as Cys73 in these studies. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.