Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes

J Mol Recognit. Jul-Aug 2009;22(4):307-18. doi: 10.1002/jmr.949.


The 2.4 A crystal structure of the beta(2)-adrenergic receptor (beta(2)AR) in complex with the high-affinity inverse agonist (-)-carazolol provides a detailed structural framework for the analysis of ligand recognition by adrenergic receptors. Insights into agonist binding and the corresponding conformational changes triggering G-protein coupled receptor (GPCR) activation mechanism are of special interest. Here we show that while the carazolol pocket captured in the beta(2)AR crystal structure accommodates (-)-isoproterenol and other agonists without steric clashes, a finite movement of the flexible extracellular part of TM-V helix (TM-Ve) obtained by receptor optimization in the presence of docked ligand can further improve the calculated binding affinities for agonist compounds. Tilting of TM-Ve towards the receptor axis provides a more complete description of polar receptor-ligand interactions for full and partial agonists, by enabling optimal engagement of agonists with two experimentally identified anchor sites, formed by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Further, receptor models incorporating a flexible TM-V backbone allow reliable prediction of binding affinities for a set of diverse ligands, suggesting potential utility of this approach to design of effective and subtype-specific agonists for adrenergic receptors. Systematic differences in capacity of partial, full and inverse agonists to induce TM-V helix tilt in the beta(2)AR model suggest potential role of TM-V as a conformational "rheostat" involved in the whole spectrum of beta(2)AR responses to small molecule signals.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic beta-2 Receptor Agonists*
  • Adrenergic beta-2 Receptor Antagonists
  • Albuterol / chemistry
  • Albuterol / pharmacology
  • Amphetamines / chemistry
  • Amphetamines / pharmacology
  • Binding Sites
  • Catechols / chemistry
  • Catechols / pharmacology
  • Dopamine / chemistry
  • Dopamine / pharmacology
  • Drug Partial Agonism*
  • Hydroxyquinolines / chemistry
  • Hydroxyquinolines / pharmacology
  • Isoproterenol / chemistry
  • Isoproterenol / pharmacology*
  • Kinetics
  • Ligands
  • Models, Molecular
  • Pliability / drug effects
  • Propanolamines / chemistry
  • Propanolamines / pharmacology*
  • Protein Structure, Secondary
  • Receptors, Adrenergic, beta-2 / chemistry*
  • Structure-Activity Relationship
  • Thermodynamics


  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-2 Receptor Antagonists
  • Amphetamines
  • Catechols
  • Hydroxyquinolines
  • Ligands
  • Propanolamines
  • Receptors, Adrenergic, beta-2
  • carazolol
  • carmoterol
  • Isoproterenol
  • catechol
  • Albuterol
  • Dopamine