Conformational States of AChBP revealed by X-ray crystal Structures of bound nAChR Agonists. Antagonists and Non- competitive ligands.
作者单位：Dept of Pharmacology UCSD CNRS Marseille Dept of Chemistry and Biochemistry UCSD CNRS Marseille CNRS Marseille Dept of Pharmacology UCSD
会议名称：《第十五届国际药理学大会》
会议日期：2006年
学科分类：1006[医学-中西医结合] 10[医学] 100602[医学-中西医结合临床]
摘 要：正 We use the acetylcholine binding protein （AChBP） from mollusks as a soluble surrogate for the extracellular ligand binding domain of nicotinic acetylcholine receptors （ nAChR）. Ligand binding in the nAChR extracellular domain induces conformational states that allosterically open an ion channel. nAChR states have not been studied at atomic resolution. We have solved X- ray crystal structures of receptor agonists, antagonists and non- competitive ligand bound to AChBP. These structures reveal large conformation changes in the ligand binding pocket and distinct interface binding surfaces. Conformational changes in loop C reveal a general mechanism for agonism and partial agonism. X- ray structures of noncompetitivereceptor ligands galanthamine. cocaine, and thienyl - cylohexylpiperidine（TCP） in complex with AChBP reveal valuable information for accurately describing non- competitive receptor modulation. A crystal structure of apo AChBP is presented and compared to that of bound agonists, lobeline and epibatidine. and antagonists, alpha-conotoxin Iml and methyllycaconitine.