Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Biophysics Program, Departments of Computer Science, Structural Biology, and Molecular and Cellular Physiology, and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
Nat Struct Mol Biol. 2018 Oct;25(10):981-987. doi: 10.1038/s41594-018-0137-2. Epub 2018 Oct 5.
The σ receptor is a poorly understood membrane protein expressed throughout the human body. Ligands targeting the σ receptor are in clinical trials for treatment of Alzheimer's disease, ischemic stroke, and neuropathic pain. However, relatively little is known regarding the σ receptor's molecular function. Here, we present crystal structures of human σ 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 σ 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 σ agonism.
σ 受体是一种尚未被充分了解的膜蛋白，在人体全身表达。靶向 σ 受体的配体正在进行临床试验，用于治疗阿尔茨海默病、缺血性中风和神经性疼痛。然而，关于 σ 受体的分子功能，人们知之甚少。在这里，我们展示了与拮抗剂氟哌啶醇和 NE-100 以及激动剂 (+)-戊噻嗪结合的人 σ 受体的晶体结构，其晶体分辨率分别为 3.1Å、2.9Å 和 3.1Å。这些结构揭示了激动剂的独特结合构象。结构和伴随的分子动力学 (MD) 模拟确定了受体中激动剂诱导的结构重排。此外，我们表明，配体与 σ 的结合是一个多步骤的过程，其受到受体构象变化的限制。我们使用 MD 模拟重建了一个涉及两个主要构象变化的配体结合途径。这些数据为理解 σ 激动剂的分子基础提供了一个框架。
