StAR-related lipid transfer domain protein 6, or StarD6, is a member of the steroidogenic acute regulatory protein family. Previous work from Letourneau et. al revealed the solution structure of this protein and demonstrated that StarD6 specifically binds testosterone, a steroid hormone. Molecular dynamic simulations revealed several key amino acid residues that may be involved in ligand-binding. We propose that these amino acids residues are crucial for not only the binding of testosterone, but for other known StarD6 ligands such as cholesterol and pregnanolone. Using a molecular modeling program called Molecular Operating Environment (MOE), we determined that an asparagine residue at position 191 (Asn191) not only forms a hydrogen bond with the carbonyl oxygen atom located on C3 of testosterone, but also with the carbonyl or hydroxyl oxygen at this position on other StarD6 ligands. Substitution of this residue with isoleucine (Ile), an amino acid that is incapable of forming a hydrogen bond, resulted in a lower calculated binding affinity for known StarD6 ligands. Recently, Kim et. al correlated a single nucleotide polymorphism in the StarD6 promoter with Alzheimer’s Disease (AD). Since steroid hormones such as dehydroepiandrosterone (DHEA) and allopregnanolone are also implicated in the onset and progression of this disease, we tested the validity of these compounds as StarD6 ligands. Both ligands are predicted to bind to StarD6 in a similar fashion as testosterone, requiring formation of a hydrogen bond with Asn191.<br/>

Using MOE to investigate potential ligands for StarD6

2019 Spring National Meeting

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