Evolution of structure‐function relationships in modern estrogen receptors and the reconstructed Ancestral Steroid Receptor 1

Abstract

Ancestral Steroid Receptor 1 (AncSR1) is a reconstructed nuclear receptor protein that gave rise to the steroid hormone receptor (SR) family and which is believed to have predated the divergence of vertebrates from chordates 525 million years ago. AncSR1 is a transcription factor that regulates the expression of proteins implicated in a broad array of biological functions, including reproduction and immunity. AncSR1's ligand binding domain has high specificity for steroid ligands with aromatized A rings and can recognize such molecules in nanomolar quantities. The evolution of specificity by the ligand binding domain led to the divergence of other subclasses of the steroid receptor family. However, AncSR1 (in addition to all proteins within the SR family) follows the minimal specificity model, evolving greater specificity only when it becomes advantageous to discriminate between the various ligands to which it is exposed. The Minnetonka MSOE CBM SMART team used 3D modeling and printing technology to examine structure‐function relationships and AncSR1's place in the evolution of SR proteins. AncSR1 was overlaid with modern estrogen receptors to explore structural evolution in the family and compared with previous findings to determine relation of structural evolution to function. Active study of structural evolution in AncSR1 and the broader SR family is leading to the development of improved pharmaceutical ligands.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.