Research Abstract


Efficacy of the β2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region

2012年9月4日 Nature Communications 3 : 1045 doi: 10.1038/ncomms2046


幸福 裕1,2, 上田 卓見1, 奥出 順也1, 白石 勇太郎1, 近藤 啓太1, 前田 正洋3, 辻下 英樹3 & 嶋田 一夫1,4

  1. 東京大学大学院 薬学系研究科
  2. バイオ産業情報化コンソーシアム
  3. 塩野義製薬株式会社
  4. 産業技術総合研究所(AIST)バイオメディシナル情報研究センター
Many drugs that target G-protein-coupled receptors (GPCRs) induce or inhibit their signal transduction with different strengths, which affect their therapeutic properties. However, the mechanism underlying the differences in the signalling levels is still not clear, although several structures of GPCRs complexed with ligands determined by X-ray crystallography are available. Here we utilized NMR to monitor the signals from the methionine residue at position 82 in neutral antagonist- and partial agonist-bound states of β2-adrenergic receptor (β2AR), which are correlated with the conformational changes of the transmembrane regions upon activation. We show that this residue exists in a conformational equilibrium between the inverse agonist-bound states and the full agonist-bound state, and the population of the latter reflects the signal transduction level in each ligand-bound state. These findings provide insights into the multi-level signalling of β2AR and other GPCRs, including the basal activity, and the mechanism of signal transduction mediated by GPCRs.