Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor

Nat Chem Biol. 2016 Sep;12(9):709-16. doi: 10.1038/nchembio.2126. Epub 2016 Jul 11.


G-protein-coupled receptor (GPCR) ligands function by stabilizing multiple, functionally distinct receptor conformations. This property underlies the ability of 'biased agonists' to activate specific subsets of a given receptor's signaling profile. However, stabilizing distinct active GPCR conformations to enable structural characterization of mechanisms underlying GPCR activation remains difficult. These challenges have accentuated the need for receptor tools that allosterically stabilize and regulate receptor function through unique, previously unappreciated mechanisms. Here, using a highly diverse RNA library combined with advanced selection strategies involving state-of-the-art next-generation sequencing and bioinformatics analyses, we identify RNA aptamers that bind a prototypical GPCR, the β2-adrenoceptor (β2AR). Using biochemical, pharmacological, and biophysical approaches, we demonstrate that these aptamers bind with nanomolar affinity at defined surfaces of the receptor, allosterically stabilizing active, inactive, and ligand-specific receptor conformations. The discovery of RNA aptamers as allosteric GPCR modulators significantly expands the diversity of ligands available to study the structural and functional regulation of GPCRs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / drug effects
  • Aptamers, Nucleotide / chemistry
  • Aptamers, Nucleotide / metabolism*
  • Benzoxazines / chemistry
  • Benzoxazines / pharmacology
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Receptors, Adrenergic, beta-2 / chemistry
  • Receptors, Adrenergic, beta-2 / metabolism*


  • Aptamers, Nucleotide
  • BI167107
  • Benzoxazines
  • Receptors, Adrenergic, beta-2