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 language | English (US) |
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Pages (from-to) | 307-318 |
Number of pages | 12 |
Journal | Journal of Molecular Recognition |
Volume | 22 |
Issue number | 4 |
DOIs | |
State | Published - Jul 2009 |
Keywords
- Activation
- Adrenergic
- Agonist
- Antagonist
- Binding energy
- Flexible docking
- G-protein
- GPCR
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology