Not simple analogues, but ligands for biological switches

A while ago I blogged about a paper where a set of structures analogous to estrogen were made. Now a follow-up paper has appeared in Protein Engineering, Design and Selection. The aim was actually not to make simple analogues of estrogen, but to use the compounds to create specific receptor proteins.

Starting from the human estrogen receptor α, the authors employed directed evolution: they changed the residues in proximity of the ligand by mutagenesis, screened the resulting mutants, and selected the best receptor mutants for the next round. After the third round of directed evolution, they came up with an optimized mutant that bound to CV3320 with an EC50 of 55 nM, while the affinity to 17β-estradiol was reduced by a factor of 10 (4 nM).

CV3320 and estradiol

While the authors admit that the selectivity over 17β-estradiol could still be improved, it still is a nice piece of work that demonstrates the power of directed evolution. This way, a protein receptor for a substrate that does not occur in nature can be made. Such a receptor can be used to make biological switches.

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