Spalding Tracy A, Trotter Carol, Skjaerbaek Niels, Messier Terri L, Currier Erika A, Burstein Ethan S, Li Donghui, Hacksell Uli, Brann Mark R
ACADIA Pharmaceuticals, Inc., San Diego, California 92121, USA.
Mol Pharmacol. 2002 Jun;61(6):1297-302. doi: 10.1124/mol.61.6.1297.
Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M(1) muscarinic receptor agonist from a novel structural class. Using a series of chimeric receptors, we demonstrated that this ligand activates the receptor through a region that is not conserved among receptor subtypes, explaining its unprecedented selectivity. This region of the receptor is distinct from the conserved region that is recognized by traditional ligands. The finding that receptors for small-molecule transmitters can have multiple, structurally distinct activation sites has broad implications for the study of receptor structure/function and the potential for the discovery of novel ligands with high selectivity.
受体具有保守性良好的区域，可被激素和神经递质识别并激活。大多数药物会与这些位点结合，模拟或阻断天然配体的作用。通过高通量功能筛选，我们从一个新型结构类别中鉴定出一种强效且选择性的M(1)毒蕈碱受体激动剂。利用一系列嵌合受体，我们证明这种配体通过受体亚型间不保守的区域激活受体，这解释了其前所未有的选择性。受体的这一区域与传统配体识别的保守区域不同。小分子递质的受体可具有多个结构不同的激活位点这一发现，对受体结构/功能研究以及发现具有高选择性的新型配体的潜力具有广泛影响。
