Department of Medicine, University of California-San Francisco, San Francisco, CA, USA.
Nat Chem Biol. 2012 Aug;8(8):725-30. doi: 10.1038/nchembio.1008. Epub 2012 Jun 24.
Most of our understanding of G protein-coupled receptor (GPCR) activation has been focused on the direct interaction between diffusible ligands and their seven-transmembrane domains. However, a number of these receptors depend on their extracellular N-terminal domain for ligand recognition and activation. To dissect the molecular interactions underlying both modes of activation at a single receptor, we used the unique properties of the melanocortin-4 receptor (MC4R), a GPCR that shows constitutive activity maintained by its N-terminal domain and is physiologically activated by the peptide α-melanocyte stimulating hormone (αMSH). We find that activation by the N-terminal domain and αMSH relies on different key residues in the transmembrane region. We also demonstrate that agouti-related protein, a physiological antagonist of MC4R, acts as an inverse agonist by inhibiting N terminus-mediated activation, leading to the speculation that a number of constitutively active orphan GPCRs could have physiological inverse agonists as sole regulators.
我们对 G 蛋白偶联受体（GPCR）激活的大部分理解都集中在可扩散配体与其七跨膜结构域之间的直接相互作用上。然而，这些受体中的许多都依赖于其细胞外 N 端结构域来识别和激活配体。为了在单个受体上剖析两种激活模式的分子相互作用，我们利用了黑皮质素-4 受体（MC4R）的独特性质，MC4R 是一种 GPCR，其 N 端结构域具有组成性活性，并被肽 α-黑素细胞刺激素（αMSH）生理性激活。我们发现，N 端结构域和 αMSH 的激活依赖于跨膜区域中的不同关键残基。我们还证明，肥胖相关蛋白（AgRP）是 MC4R 的一种生理性拮抗剂，通过抑制 N 端介导的激活发挥反向激动剂的作用，这使得人们推测，许多组成性激活的孤儿 GPCR 可能只有生理反向激动剂作为唯一调节剂。
