Structural Studies and Drug Discovery Illuminate Serotonin Pharmacology

项目概要/摘要 该实验室的主要目标是提供对血清素信号传导的详细结构和功能见解， 运输，并阐明如何药物和药物调节受体和转运功能。血清素（5- 羟色胺，5-HT）调节CNS内外的许多人体生理学，包括认知， 情绪、内分泌功能和心血管发育。然而，尽管5-HT的生理和医学 重要性，原子水平的深入了解5-HT信号和运输的机制，以及药物如何相互作用 与这些分子靶点的结合，仍然很难实现。这种缺乏了解导致了药物安全 过去的问题，并极大地阻碍了许多5-HT靶点用于新型治疗应用的探索。 因此，我们的实验室专注于两个严重研究不足的5-HT靶点。实验室的第一个主要方向是 阐明5-HT 1 E受体的配体结合和活化，5-HT 1 E受体是最不了解的5-HT受体， 生理作用未知。与所有其他5-HT受体不同，没有5-HT受体的选择性化合物。 HT 1 ER，这提出了关于其结合口袋的分子结构的重要问题， 受体激活机制。为了回答这些问题，我们将确定G 蛋白偶联的5-HT 1 ER，这将提供详细的结构洞察配体结合口袋 结构，以及负责G蛋白激活的受体构象变化。第二主 该项目的重点是囊泡单胺转运蛋白2（VMAT 2），这是一种重要的储存转运蛋白， 调节神经递质信号传导，并针对从糖尿病到安非他明的各种疾病 虐待尽管它具有生物学和医学意义，但人们缺乏对它在哪里和在哪里的原子级洞察 底物、药物或药物如何结合，或它们如何调节VMAT 2功能。因此我们将 确定与各种底物和药物结合的VMAT 2的晶体结构，阐明VMAT 2的基本原理， 转运和药物调节的机制，并表征不同结合的精确结构 网站.我们将进一步利用我们在基于结构的药物发现中的分子见解， 用于未来体外研究VMAT 2（病理）生物学的生物学和化学新工具化合物 和体内。我们的研究在技术上和概念上都是创新的， 结构，药理学和药物发现方法将提供一个前所未有的观点， 两个被忽视和研究不足的5-HT药物靶点的分子机制。

Project Summary/Abstract The main goal of the lab is to provide detailed structural and functional insight into serotonin signaling and transport, and elucidate how drugs and medications modulate receptor and transporter function. Serotonin (5- hydroxytryptamine, 5-HT) regulates much of human physiology in- and outside the CNS, including cognition, mood, endocrine function and cardiovascular development. However, despite 5-HT's physiological and medical importance, atomic-level insight into the mechanisms of 5-HT signaling and transport, and how drugs interact with these molecular targets, has remained largely elusive. This lack of understanding has led to drug safety issues in the past, and greatly hindered the exploration of many 5-HT targets for novel therapeutic applications. Our lab is thus focused on two grossly understudied 5-HT targets. The first major direction of the lab is to elucidate ligand binding and activation of the 5-HT1E receptor, the least understood 5-HT receptor whose physiological role is unknown. Unlike for all other 5-HT receptors, there are no selective compounds for 5- HT1ER, which raises important questions about the molecular architecture of its binding pocket and mechanisms of receptor activation. To answer these questions, we will determine the cryoEM structure of G protein-coupled 5-HT1ER, which will provide detailed structural insight into the ligand binding pocket architecture, and the receptor's conformational changes responsible for G protein activation. The second major project is focused on the vesicular monoamine transporter 2 (VMAT2), an essential transporter for storage and regulation of neurotransmitter signaling, and target for a variety of disorders from diabetes to amphetamine abuse. Despite its biological and medical significance, there is a lack of atomic-level insight into where and how substrates, drugs, or medications bind, or how they modulate VMAT2 function. We will therefore determine crystal structures of VMAT2 bound to various substrates and drugs, elucidate fundamental mechanisms of transport and drug modulation, and characterize the precise architecture of different binding sites. We will further use our molecular insights in structure-based drug discovery, to develop pharmacologically and chemically novel tool compounds for future studies of VMAT2 (patho)biology in in vitro and in vivo. Our studies are both innovative technically and conceptually, as the unique combination of structural, pharmacological, and drug discovery approaches will provide an unprecedented view into the molecular mechanisms of two neglected and understudied 5-HT drug targets.