Analysis of full and partial agonists binding to β2- adrenergic receptor suggests a role of transmembrane helix v in agonist-specific conformational changes

Vsevolod Katritch, Kimberly A. Reynolds, Vadim Cherezov, Michael A. Hanson, Christopher B. Roth, Mark Yeager, Ruben Abagyan

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

The 2.4 å crystal structure of the β2-adrenergic receptor (β2AR) 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 β2AR 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 β2AR model suggest potential role of TM-V as a conformational "rheostat" involved in the whole spectrum of β2AR responses to small molecule signals.

Original languageEnglish (US)
Pages (from-to)307-318
Number of pages12
JournalJournal of Molecular Recognition
Volume22
Issue number4
DOIs
StatePublished - Jul 1 2009

Keywords

  • Activation
  • Adrenergic
  • Agonist
  • Antagonist
  • Binding energy
  • Flexible docking
  • G-protein
  • GPCR

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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