兴奋剂
化学
配体(生物化学)
受体
部分激动剂
G蛋白偶联受体
喷他佐辛
分子动力学
生物物理学
功能选择性
构象变化
立体化学
生物化学
药理学
生物
计算化学
吗啡
作者
Hayden R. Schmidt,Robin M. Betz,Ron O. Dror,Andrew C. Kruse
标识
DOI:10.1038/s41594-018-0137-2
摘要
The σ1 receptor is a poorly understood membrane protein expressed throughout the human body. Ligands targeting the σ1 receptor are in clinical trials for treatment of Alzheimer’s disease, ischemic stroke, and neuropathic pain. However, relatively little is known regarding the σ1 receptor’s molecular function. Here, we present crystal structures of human σ1 receptor bound to the antagonists haloperidol and NE-100, and the agonist (+)-pentazocine, at crystallographic resolutions of 3.1 Å, 2.9 Å, and 3.1 Å, respectively. These structures reveal a unique binding pose for the agonist. The structures and accompanying molecular dynamics (MD) simulations identify agonist-induced structural rearrangements in the receptor. Additionally, we show that ligand binding to σ1 is a multistep process that is rate limited by receptor conformational change. We used MD simulations to reconstruct a ligand binding pathway involving two major conformational changes. These data provide a framework for understanding the molecular basis for σ1 agonism. Crystal structures of human σ1 receptor bound to the antagonists haloperidol and NE-100, and to agonist (+)-pentazocine, alongside MD simulations, reveal a unique binding pose for, and major conformational rearrangements induced by, the agonist.
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