NRbox

NRbox, short for Nuclear Receptor box, is a short, conserved sequence motif found in transcriptional coactivators that regulate gene expression by interacting with nuclear receptors. The motif is best known as LXXLL, a four-residue pattern that enables selective binding to ligand-activated nuclear receptors.

Sequence characteristics: The canonical motif is leucine-rich, represented as L-X-X-L-L, where X denotes any amino acid. Variants with substitutions such as isoleucine or valine at one or both leucine positions, or with altered surrounding residues, have been described and can affect receptor specificity and binding strength.

Role in transcription: NR boxes mediate recruitment of coactivator proteins, such as members of the p160/SRC family and CBP/p300, to the ligand-binding domain of nuclear receptors. Upon hormone binding, the NR box often forms an alpha helix that packs into a hydrophobic groove on the receptor, stabilizing the transcriptional activation complex.

Distribution and evolution: NR boxes are found across metazoan transcriptional coactivators and can occur in multiple copies within a single protein, allowing interactions with several receptor subtypes. Their sequences show conservation of key leucine residues, yet substantial variability in surrounding residues.

Significance and research: The NR box motif is central to hormone-responsive gene regulation and is a common focus in studies of nuclear receptor signaling, coactivator function, and diseases linked to dysregulated transcription. Techniques used to study NR boxes include mutagenesis, binding assays, X-ray crystallography, and NMR.

See also: Nuclear receptor, coactivator, LXXLL motif.