# A Structure-Based Analysis of the Evolution of Transcription Factors of the FNR/CRP Family

## TL;DR

This paper uses X-ray structures to study how a family of transcription factors evolved, revealing shared features and different activation mechanisms.

## Contribution

The study identifies structural similarities and divergent allosteric mechanisms in FNR/CRP family transcription factors through X-ray analysis.

## Key findings

- Conserved phosphate-binding features suggest closer relationships among some TFs than sequence comparisons indicate.
- Three distinct allosteric activation mechanisms likely evolved independently within the TF family.
- Some TFs use salt bridges to stabilize the ligand-binding cavity, suggesting evolution from allosteric ancestors.

## Abstract

The X-ray structural analysis of the N-terminal domain cavity from eleven transcription regulators (TFs) of the Fumarate Nitrate Reduction regulator/cAMP Regulator Protein family shows several significant trends. The conservancy of effector-binding phosphate binding cassette features in three TFs suggests a closer connection among them than the one obtained through the comparison of overall amino acid sequences. Conversely, there are also three clearly different allosteric activation mechanisms, which most likely evolved independently. Interestingly, several TFs of this family adopt the DNA-binding conformation without binding any ligand; instead, the buried region corresponding to the “allosteric” cavity is partially filled with salt bridges (which is also the case for two allosteric apo TFs). One plausible conclusion from these observations is that the non-allosteric TFs evolved from an allosteric counterpart and used salt bridges to fill and stabilize the formally polar ligand-binding cavity. O2-sensing TFs share some residues in the relevant N-terminal domain cavity and might have had an already non-allosteric common ancestor.