Mechanism of β 2 AR regulation by an intracellular positive allosteric modulator

Science. 2019 Jun 28;364(6447):1283-1287. doi: 10.1126/science.aaw8981. Epub 2019 Jun 27.

Abstract

Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic β2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor's inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β2- over the β1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.

Publication types

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

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / chemistry*
  • Adrenergic beta-2 Receptor Agonists / pharmacology
  • Allosteric Regulation
  • Crystallography, X-Ray
  • Gain of Function Mutation
  • Humans
  • Phthalic Anhydrides / chemistry*
  • Phthalic Anhydrides / pharmacology
  • Receptors, Adrenergic, beta-2 / chemistry*
  • Receptors, Adrenergic, beta-2 / genetics

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Phthalic Anhydrides
  • Receptors, Adrenergic, beta-2
  • 2,2'-bis(3,4-dicarboxyphenyl)hexafluoropropane dianhydride